Substituted pyrrolopyrimidines and processes for their preparation

ABSTRACT

There are described 7H-pyrrolo[2,3-d]pyrimidine derivatives of the formula Iin which the substituents are as defined in claim 1.These compounds inhibit the tyrosine kinase activity of the receptor for the epidermal growth factor (EGF) and c-erbB2 kinase and can be used as anti-tumor agents.

The invention relates to 7H-pyrrolo[2,3-d]pyrimidine derivatives and toprocesses and novel intermediates for their preparation, topharmaceutical formulations comprising such derivatives and to the useof these derivatives as medicaments.

The invention relates to 7H-pyrrolo[2,3-d]pyrimidine derivatives of theformula I

in which n is 0 to 3,

q is 0 or 1,

R is halogen, lower alkyl, hydroxymethyl, aminomethyl, hydroxyl, loweralkanoyloxy, lower alkoxy, carboxyl, lower alkanoyl, benzoyl, loweralkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylcarbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino,N,N-di-lower alkylamino or trifluoromethyl, it being possible, if two ormore radicals R are present in the molecule, for these to be identicalto or different from one another,

one of the radicals R₁ and R₂ is hydrogen or lower alkyl,

and the other of the radicals R₁ and R₂ is

a) a radical of the formula II

 in which u is 1 to 3 and

at least one radical R₄ is amidino, guanidino, ureido, N³-loweralkylureido, N³,N³-di-lower alkylureido, N³-phenylureido,N³,N³-diphenylureido, thiocarbamoyl, thioureido, N³-loweralkylthioureido, N³,N³-di-lower alkylthioureido, loweralkoxycarbonylamino, benzyloxycarbonylamino, morpholine-4-carbonyl,piperazine-1-carbonyl, 4-lower alkylpiperazine-1-carbonyl, loweralkylsulfonylamino, benzenesulfonylamino, toluenesulfonylamino,thiophene-2-carbonylamino, furan-2-carbonylamino, benzylamino,hydroxymethyl, aminomethyl or a radical of the formula —N═C(R₅)—R₆, inwhich R₅ is hydrogen or lower alkyl and R₆ is di-lower alkylamino,piperidino, 4-lower alkylpiperazino or morpholino, and the otherradical(s) R₄ is (are) halogen, lower alkyl, hydroxyl, loweralkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, cyano, amino, loweralkanoylamino, lower alkylamino, N,N-di-lower alkylamino ortrifluoromethyl, it being possible, if two or more radicals R₄ arepresent in the molecule, for these to be identical to or different fromone another, or is

b) a radical of the formula III

 in which R₇ is lower alkoxy or benzyloxy and R₈ is hydroxyl orbenzyloxy, or is

c) amino-lower alkyl, in which the amino group is substituted by one ortwo hydroxy-lower alkyl, amino-lower alkyl, carboxy-lower alkyl, loweralkoxycarbonyl-lower alkyl, benzyloxycarbonyl-lower alkyl or benzylradicals, which in the phenyl moiety are unsubstituted or substituted byhalogen, lower alkyl, hydroxymethyl, aminomethyl, hydroxyl, loweralkanoyloxy, lower alkoxy, carboxyl, lower alkanoyl, benzoyl, loweralkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylcarbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino,N,N-di-lower alkylamino or trifluoromethyl, or is

d) piperidine-1-carbonyl, piperazine-1-carbonyl, 4-loweralkylpiperazine-1-carbonyl, morpholine-4-carbonyl, thiocarbamoyl, aheterocyclic radical bonded via a ring carbon atom and having five ringmembers and 1-4 ring heteroatoms, selected from oxygen, nitrogen andsulfur, or is

e) 4-lower alkylpiperazinomethyl or a lower alkyl radical which issubstituted by a heterocyclic radical other than piperazinyl and havingfive or six ring members and 1-4 ring heteroatoms, selected from oxygen,nitrogen and sulfur, or is

f) a radical of the formula —CH═N—OR₉ in which R₉ is hydrogen or loweralkyl, or

g) if q is 1, additionally to the definitions given above in thesections a) to f) can also be phenyl which is substituted by halogen,lower alkyl, trifluoromethyl or lower alkoxy, and R₃ is hydrogen, loweralkyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl orN,N-di-lower alkylcarbamoyl,

and their salts.

The prefix “lower” used hereinbefore and hereinafter denotes a radicalhaving up to and including a maximum of 7, especially up to andincluding a maximum of 4, and in particular having 1 or 2, carbon atoms.

Preferably, n is 0 or especially 1. When there is only one substituentR, this substituent is preferably in the 3-position on the phenyl ring.When two substituents R are present, these substituents are preferablyin the 3- and 4-positions.

Halogen R is bromine, iodine or preferably fluorine or chlorine. When nis 1, R is preferably chlorine.

Lower alkyl is, for example, methyl.

Lower alkanoyloxy is, for example, acetoxy.

Lower alkoxy is, for example, methoxy.

Lower alkanoyl is, for example, acetyl.

Lower alkoxycarbonyl is, for example, methoxycarbonyl.

N-Lower alkylcarbamoyl is, for example, N-methylcarbamoyl,N-(n-butyl)carbamoyl or N-(3-methylbut-1-yl)carbamoyl. N,N-Di-loweralkylcarbamoyl is, for example, N,N-di-methylcarbamoyl.

Lower alkanoylamino is, for example, acetylamino.

Lower alkylamino is, for example, methylamino.

N,N-Di-lower alkylamino is, for example, dimethylamino.

Lower alkoxycarbonylmethoxy is, for example, methoxycarbonylmethoxy.

The radical R₁ is preferably hydrogen.

The symbol u is preferably 1. In this case, the radical R₄ is preferablyin the 3- or 4-position of the phenyl ring.

Amidino is a radical of the formula —C(═NH)—NH₂.

Guanidino is a radical of the formula —NH—C(═NH)—NH₂.

Ureido is a radical of the formula —NH—C(═O)—NH₂.

N³-Lower alkyl ureido is a radical of the formula —NH—C(═O)—NH-loweralkyl, preferably N³-ethylureido.

N³, N³-Di-lower alkylureido is a radical of the formula—NH—C(═O)—N(lower alkyl)₂.

N³-Phenylureido is a radical of the formula —NH—C(═O)—NH-phenyl.

N³, N³-Diphenylureido is a radical of the formula —NH—C(═O)—N(phenyl)₂.

Thioureido is a radical of the formula —NH—C(═S)—NH₂.

N³-Lower alkylthioureido is a radical of the formula —NH—C(═S)—NH-loweralkyl, preferably N³-methylthioureido.

N³,N³-Di-lower alkylthioureido is a radical of the formula—NH—C(═S)—N(lower alkyl)₂.

Lower alkoxycarbonylamino is, for example, methoxycarbonylamino,ethoxycarbonylamino, isopropyloxycarbonylamino or2-methylpropyloxycarbonylamino.

Morpholine-4-carbonyl is also called morpholinocarbonyl.

4-Lower alkylpiperazine-1-carbonyl is preferably4-methylpiperazine-1-carbonyl.

Lower alkylsulfonylamino is preferably methylsulfonylamino,ethylsulfonylamino or isopropylsulfonylamino.

The radical of the formula —N═C(R₅)—R₆, in which R₅ is hydrogen and R₆is di-lower alkylamino, is called di-lower alkylaminomethylenamino.Corresponding radicals in which R₆ is piperidino, 4-loweralkylpiperazino or morpholino are called R₆-methylenamino radicals, inwhich R₆ is defined as above, e.g. as piperidinomethylamino.

R₅ is preferably hydrogen.

Di-lower alkylamino R₆ is preferably dimethylamino or diethylamino.

4-Lower alkylpiperazino is 4-lower alkylpiperazin-1-yl, preferably4-methylpiperazin-1-yl.

Morpholino is 4-morphotinyl.

Lower alkoxy R₇ is preferably methoxy.

Amino-lower alkyl R₁ or R₂ in which the amino group is substituted byone or two hydroxy-lower alkyl, amino-lower alkyl, carboxy-lower alkyl,lower alkoxycarbonyl-lower alkyl, benzyloxycarbonyl-lower alkyl orbenzyl radicals which in the phenyl moiety are unsubstituted orsubstituted by halogen, lower alkyl, hydroxymethyl, aminomethyl,hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkanoyl,benzoyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylcarbamoyl, cyano, amino, lower alkanoylamino, loweralkylamino, N,N-di-lower alkylamino or trifluoromethyl, is preferablyappropriately substituted aminomethyl.

Amino-lower alkyl R₁ or R₂ in which the amino group is substituted byone or two hydroxy-lower alkyl radicals is preferably, for example, aradical of the formula —CH₂—NH(CH₂—CH₂)₂.

Amino-lower alkyl R₁ or R₂ in which the amino group is substituted byone or two benzyl radicals which in the phenyl moiety are unsubstitutedor substituted by halogen, lower alkyl, hydroxymethyl, aminomethyl,hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkanoyl,benzoyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylcarbamoyl, cyano, amino, lower alkanoylamino, loweralkylamino, N,N-di-lower alkylamino or trifluoromethyl, is preferably,for example, a radical of the formula —CH₂—NH—CH₂—C₆H₄—OCH₃,

such as, in particular, 4-methoxyphenylmethylaminomethyl, or4-hydroxyphenylmethylaminomethyl.

Thiocarbamoyl is the radical of the formula —C(═S)—NH₂ and is alsocalled aminothiocarbonyl.

A heterocyclic radical R₁ or R₂ bonded via a ring carbon atom and havingfive ring members and 1-4 ring heteroatoms, selected from oxygen,nitrogen and sulfur, is unsubstituted or substituted, e.g. pyrrolyl,thienyl, furyl or preferably tetrazol-5-yl which is unsubstituted orsubstituted by lower alkyl, or thiazol-2-yl which is unsubstituted orsubstituted by lower alkoxyphenyl, e.g. thiazol-2-yl,4-(4-methoxyphenyl)thiazol-2-yl, 4-ethylthiazol-2-yl or4,5-dimethylthiazol-2-yl.

Tetrazol-5-yl is 1H-tetrazol-5-yl or the tautomeric 2H-tetrazol-5-yl ora mixture of these two tautomeric forms.

Tetrazol-5-yl substituted by lower alkyl is N¹-lower alkyltetrazol-5-ylor N²-lower alkyltetrazol-5-yl, in particular 1-methyltetrazol-5-yl or2-methyltetrazol-5-yl.

A heterocyclic radical other than piperazinyl and having five or sixring members and 1-4 ring heteroatoms, selected from oxygen, nitrogenand sulfur, is such an unsubstituted or substituted radical, e.g.pyrrolyl, thienyl, furyl, tetrazol-5-yl which is unsubstituted orsubstituted by lower alkyl; thiazol-2-yl which is unsubstituted orsubstituted by lower alkoxyphenyl, or morpholino or 4-loweralkylpiperazin-1-yl.

Lower alkyl R₁ or R₂ which is substituted by such a heterocyclic radicalis preferably appropriately substituted methyl, preferably4-methylpiperazin-1-ylmethyl or morpholinomethyl.

The radical —CH═N—OR₉ R₁ or R₂ can be present in the trans- orcis-configuration.

Phenyl R₁ or R₂ which is substituted by halogen, lower alkyl,trifluoromethyl or lower alkoxy is, for example, 4-methoxyphenyl. R₁ orR₂ can only be phenyl which is substituted in this way if in formula Ithe symbol q is 1.

R₃ is preferably methyl.

Salts of compounds of the formula I are especially acid addition saltswith organic or inorganic acids, especially the pharmaceuticallyacceptable, non-toxic salts. Suitable inorganic acids are, for example,carbonic acid (preferably in the form of carbonates orhydrogencarbonates); hydrohalic acids, such as hydrochloric acid;sulfuric acid; or phosphoric acid. Suitable organic acids are, forexample, carboxylic, phosphonic, sulfonic or sulfamic acids, for exampleacetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoicacid, glycolic acid, lactic acid, 2-hydroxybutyric acid, gluconic acid,glucosemonocarboxylic acid, fumaric acid, succinic acid, adipic acid,pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid,citric acid, glucaric acid, galactaric acid, amino acids, such asglutamic acid, aspartic acid, N-methylglycine, acetylaminoacetic acid,N-acetylasparagine or N-acetylcystine, pyruvic acid, acetoacetic acid,phosphoserine, 2- or 3-glycerophosphoric acid, glucose-6-phosphoricacid, glucose-1-phosphoric acid, fructose-1,6-bisphosphoric acid, maleicacid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid,adamantanecarboxylic acid, benzoic acid, salicylic acid, 1- or3-hydroxynaphthyl-2-carboxylic acid, 3,4,5-trimethoxybenzoic acid,2-phenoxybenzoic acid, 2-acetoxybenzoic acid, 4-aminosalicylic acid,phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid,nicotinic acid, isonicotinic acid, glucuronic acid, galacturonic acid,methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid,ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonicacid, 1,5-naphthalenedisulfonic acid, 2-, 3- or 4-methylbenzenesulfonicacid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid,N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamicacid, or other organic protonic acids, such as ascorbic acid.

Compounds of the formula I having at least one acid group, for example afree carboxyl group, are capable of forming internal salts or metal orammonium salts, such as alkali metal or alkaline earth metal salts, forexample sodium, potassium, magnesium or calcium salts, or ammonium saltswith ammonia or suitable organic amines, such as tertiary monoamines,for example triethylamine or tri(2-hydroxyethyl)amine, or heterocyclicbases, for example N-ethylpiperidine or N,N′-dimethylpiperazine.

For isolation or purification purposes it is also possible to usepharmaceutically unsuitable salts, for example picrates or perchlorates.Only salts that are pharmaceutically acceptable and non-toxic (at theappropriate doses) are used therapeutically and these salts aretherefore preferred.

In view of the close relationship between the novel compounds in freeform and in the form of their salts, including those salts that can beused as intermediates, for example in the purification or identificationof the novel compounds, hereinbefore and hereinafter the free compoundsare to be understood as meaning also the corresponding salts, asappropriate and expedient.

The compounds of the formula I have valuable pharmacologically usefulproperties. In particular they display specific inhibitory activitiesthat are of pharmacological interest. They are effective primarily asprotein tyrosine kinase inhibitors and/or (furthermore) as inhibitors ofprotein serine/threonine kinases; they exhibit, for example, potentinhibition of the tyrosine kinase activity of the receptor for theepidermal growth factor (EGF) and of c-erbB2 kinase. Thesereceptor-specific enzyme activities play a key role in signaltransmission in a large number of mammalian cells, including humancells, especially epithelial cells, cells of the immune system and cellsof the central and peripheral nervous system. For example, in variouscell types, EGF-induced activation of receptor-associated proteintyrosine kinase (EGF-R-PTK) is a prerequisite for cell division and thusfor the proliferation of the cell population. An increase in the numberof EGF-receptor-specific tyrosine kinase inhibitors thus inhibits theproliferation of the cells. The same applies analogously to the otherprotein kinases mentioned hereinbefore and hereinafter.

In addition to or instead of inhibiting EGF receptor protein tyrosinekinase, the compounds of the formula I also inhibit to varying extentsother protein tyrosine kinases that are involved in signal transmissionmediated by trophic factors, for example abl kinase, especially v-ablkinase, kinases from the family of the src kinases, especially c-srckinase, Ick, fyn; other kinases of the EGF family, for example c-erbB2kinase (HER-2), c-erbB3 kinase, c-erbB4 kinase; members of the family ofthe PDGF receptor protein tyrosine kinases, for example PDGF receptorkinase, CSF-1 receptor kinase, Kit receptor kinase, VEGF receptor kinaseand FGF receptor kinase; the receptor kinase of the insulin-like growthfactor (IGF-1 kinase), and serine/threonine kinases, for example proteinkinase C or cdc kinases, all of which play a part in growth regulationand transformation in mammalian cells, including human cells.

The inhibition of EGF-receptor-specific protein tyrosine kinase(EGF-R-PTK) can be demonstrated using known methods, for example usingthe recombinant intracellular domain of the EGF receptor (EGF-R ICD;see, for example, E. McGlynn et al., Europ. J. Biochem. 207, 265-275(1992)). Compared with the control without inhibitor, the compounds ofthe formula I inhibit the enzyme activity by 50% (IC₅₀), for example ina concentration of from 0.0005 to 1 μM, especially from 0.001 to 0.1 μM.

The action of the compounds of the formula I on EGF-stimulated cellulartyrosine phosphorylation in the EGF-receptor can be determined in thehuman A431 epithelial carcinoma cell line by means of an ELISA which isdescribed in U. Trinks et al., J. Med. Chem. 37:7, 1015-1027 (1994). Inthis test (EGFR-ELISA) the compounds of the formula I exhibit an IC₅₀ ofapproximately 0.001 to 1 μM.

Stimulation of quiescent BALB/c3T3 cells with EGF rapidly induces theexpression of c-fos mRNA. Pretreatment of the cells with a compound ofthe formula I before the stimulation with EGF inhibits c-fos expressionat an IC₅₀ of approximately from 0.001 to 0.1 μM. This test procedure islikewise described in U. Trinks et al., J. Med. Chem. 37:7,1015-1027(1994).

In the micromolar range too, the compounds of the formula I alsoexhibit, for example, inhibition of the cell growth of EGF-dependentcell lines, for example the epidermoid BALB/c mouse keratinocyte cellline (see Weissmann, B. A., and Aaronson, S. A., Cell 32, 599 (1983)) orthe A431 cell line, which are recognized as useful standard sources ofEGF-dependent epithelial cells (see Carpenter, G., and Zendegni, J.Anal. Biochem. 153, 279-282 (1985)). In a known test method (see Meyeret al., Int. J. Cancer 43, 851 (1989)), the inhibitory activity of thecompounds of the formula I is determined, briefly, as follows: BALB/MKcells (10 000/microtiter plate well) are transferred to 96-wellmicrotiter plates. The test compounds (dissolved in DMSO) are added in aseries of concentrations (dilution series) in such a manner that thefinal concentration of DMSO is not greater than 1% (v/v). After theaddition, the plates are incubated for three days during which thecontrol cultures without test compound are able to undergo at leastthree cell-division cycles. The growth of the MK cells is measured bymeans of Methylene Blue staining: after the incubation the cells arefixed with glutaraldehyde, washed with water and stained with 0.05%Methylene Blue. After a washing step the stain is eluted with 3% HCl andthe optical density per well of the microtiter plate is measured using aTitertek Multiscan at 665 nm. IC₅₀ values are determined by acomputer-aided system using the formula:

IC₅₀=[(OD_(test)−OD_(start))/(OD_(control)−OD_(start))]×100.

The IC₅₀ value in these experiments is given as that concentration ofthe test compound in question that results in a cell count that is 50%lower than that obtained using the control without inhibitor. Thecompounds of the formula I display inhibitory activity in the micromolarrange, for example an IC₅₀ of approximately from 0.1 to 1 μM.

The compounds of the formula I display inhibition of the growth of tumorcells also in vivo, as shown, for example, by the test described below:the test is based on inhibition of the growth of the human epidermoidcarcinoma A431 (ATCC No. CRL 1555; American Type Culture Collection,Rockville, Md., USA; see Santon, J. B., et al., Cancer Research 46,4701-4705 (1986) and Ozawa, S., et al., Int. J. Cancer 40, 706-710(1987)), which is transplanted into female BALB/c nude mice(Bomholtgard, Denmark). This carcinoma exhibits a growth that correlateswith the extent of the expression of the EGF-receptor. In theexperiment, tumors having a volume of approximately 1 cm³ cultured invivo are surgically removed from experimental animals under sterileconditions. These tumors are comminuted and suspended in 10 volumes(w/v) of phosphate-buffered saline. The suspension is injected s.c. (0.2ml/mouse in phosphate-buffered saline) into the left flank of theanimals. Alternatively, 1×10⁶ cells from an in vitro culture in 0.2 mlof phosphate-buffered saline can be injected. Treatment with testcompounds of the formula I is started 5 or 7 days after transplantation,when the tumors have reached a diameter of 4-5 mm. The active compoundin question is administered (in different doses for different animalgroups) once a day for 15 successive days. The tumor growth isdetermined by measuring the diameter of the tumors along three axes thatare perpendicular to each other. The tumor volumes are calculated usingthe known formula p×L×D²/6 (see Evans, B. D., et al., Brit. J. Cancer45, 466-8 (1982)). The results are given as treatment/controlpercentages (T/C×100=T/C %). At a dose of from 3 to 50 mg/kg of activeingredient, distinct inhibition of the tumor growth is found, forexample T/C % values of less than 10, which indicates strong inhibitionof tumor growth.

As well as or instead of inhibiting EGF-receptor protein tyrosinekinase, the compounds of the formula I also inhibit other proteintyrosine kinases that are involved in signal transmission mediated bytrophic factors, for example abl kinase, such as especially v-abl kinase(IC₅₀ for example from 0.01 to 5 μM), kinases from the family of the srckinases, such as especially c-src kinase (IC₅₀ for example from 0.1 to10 μM) and c-erbB2 kinase (HER-2), and serine/threonine kinases, forexample protein kinase C, all of which are involved in growth regulationand transformation in mammalian cells, including human cells.

The abovementioned inhibition of v-abl tyrosine kinase is determined bythe methods of N. Lydon et al., Oncogene Research 5, 161-173 (1990) andJ. F. Geissler et al., Cancer Research 52, 4492-4498 (1992). In thesemethods [Val⁵]-angiotensin II and [-γ−³²P]-ATP are used as substrates.

The inhibition of c-erbB2 tyrosine kinase (HER-2) can be determined, forexample, analogously to the method used for EGF-R-TPK (see C. House etal., Europ. J. Biochem 140, 363-367 (1984)). The c-erbB2 kinase can beisolated, and its activity determined, by means of protocols known perse, for example in accordance with T. Akiyama et al., Science 232, 1644(1986).

The compounds of the formula I which inhibit the tyrosine kinaseactivity of the receptor for the epidermal growth factor (EGF) orfurthermore of the other protein tyrosine kinases mentioned aretherefore useful, for example, in the treatment of benign or malignanttumors. They are capable of effecting tumor regression and of preventingthe formation of tumor metastases and the growth of micrometastases.They can be used especially in the case of epidermal hyperproliferation(psoriasis), in the treatment of neoplasias of epithelial character,e.g. mammary carcinomas, and in leukemias. In addition, the compounds ofthe formula I (especially the novel compounds) can be used in thetreatment of those disorders of the immune system in which several or,especially, individual protein tyrosine kinases and/or (furthermore)protein serine/threonine kinases are involved; these compounds of theformula I can also be used in the treatment of those disorders of thecentral or peripheral nervous system in which signal transmission byseveral or, especially, a single protein tyrosine kinase and/or(furthermore) protein serine/threonine kinases is involved.

In general, the present invention relates also to the use of thecompounds of the formula I for the inhibition of the protein kinasesmentioned.

The compounds according to the invention can be used both alone and incombination with other pharmacologically active compounds, for exampletogether with inhibitors of the enzymes of polyamine synthesis,inhibitors of protein kinase C, inhibitors of other tyrosine kinases,cytokines, negative growth regulators, for example TGF-β or IFN-β,aromatase inhibitors, antioestrogens and/or cytostatic agents.

In the preferred subjects of the invention mentioned hereinafter,general definitions can be replaced by the more specific definitionsgiven at the beginning, where appropriate and expedient.

Preferred compounds of the formula I are those according to claim 1, inwhich R₁ is hydrogen,

R₂ is pyrrolyl, thienyl, furyl, tetrazol-5-yl which is unsubstituted orsubstituted by lower alkyl, or thiazol-2-yl which is unsubstituted orsubstituted by lower alkoxyphenyl, or methyl which is substituted bypyrrolyl, thienyl, furyl, morpholino, 4-lower alkylpiperazin-1-yl,tetrazol-5-yl which is unsubstituted or substituted by lower alkyl, orthiazol-2-yl which is unsubstituted or substituted by loweralkoxyphenyl, and the other radicals and symbols are as defined above,

and their salts.

Very preferred compounds of the formula I are those in which

n is 0 or 1,

q is 0 or 1,

R is chlorine,

R₁ is hydrogen,

R₂ is

a) a radical of the formula II

 in which u is 1 and

R₄ is N³-lower alkylureido, N³-phenylureido, N³-lower alkylthioureido,lower alkoxycarbonylamino, benzyloxycarbonylamino,morpholine-4-carbonyl, piperazine-1-carbonyl, 4-loweralkylpiperazine-1-carbonyl, lower alkylsulfonylamino,benzenesulfonylamino, toluenesulfonylamino, furan-2-carbonylamino,thiophene-2-carbonylamino, benzylamino, hydroxymethyl or a radical ofthe formula —N═C(R₅)—R₆ in which R₅ is hydrogen or lower alkyl and R₆ isdi-lower alkylamino, piperidino, 4-lower alkylpiperazino or morpholino,or is

b) a radical of the formula III

 in which R₇ is lower alkoxy and R₈ is hydroxyl or benzyloxy, or is

c) aminomethyl in which the amino group is substituted by one or twohydroxy-lower alkyl or benzyl radicals which in the phenyl moiety areunsubstituted or substituted by hydroxyl or lower alkoxy, or is

d) piperazine-1-carbonyl, 4-lower alkylpiperazine-1-carbonyl,morpholine-4-carbonyl, thiocarbamoyl, thiazol-2-yl,4-(4-methoxyphenyl)thiazol-2-yl, 4-ethylthiazol-2-yl,4,5-dimethylthiazol-2-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl or1-methyltetrazol-5-yl, or is

e) 4-lower alkylpiperazinomethyl or morpholinomethyl, or is

f) a radical of the formula —CH═N—OR₉, in which R₉ is hydrogen or loweralkyl, or

g) if q is 1, additionally to the definitions given above in sections a)to f) can also be phenyl which is substituted by lower alkoxy, and

R₃is hydrogen or lower alkyl,

and their salts.

The most preferred compounds of the formula I are those described in theExamples and their pharmaceutically acceptable salts.

The compounds of the formula I and their salts are prepared by processesknown per se. The process according to the invention comprises

a) reacting a pyrrolo[2,3-d]pyrimidine derivative of the formula IV

 in which X is a suitable leaving group, Z is hydrogen or 1-aryl-loweralkyl and the other substituents are as defined above for compounds ofthe formula I, free functional groups present in the radicals R₁ and R₂if necessary being protected by easily removable protective groups, withan aniline derivative of the formula V

 in which R, R₃, n and q are as defined above for compounds of theformula I, free functional groups present in the radical R if necessarybeing protected by easily removable protective groups, and removingprotective groups present and, if present, the 1-aryl-lower alkylradical Z, or

b) reacting a pyrrolo[2,3-d]pyrimidin-4-one derivative of the formula VI

 in which Z′ is 1-aryl-lower alkyl and R₁ and R₂ are as defined abovefor compounds of the formula I, free functional groups present in theradicals R₁ and R₂ if necessary being protected by easily removableprotective groups, in the presence of a dehydrating agent and a tertiaryamine, with a phenylamine of the formula V above and removing protectivegroups present, or

c) for the preparation of a compound of the formula I in which theradical R is hydroxyl or in which one of the radicals R₁ or R₂ isamino-lower alkyl in which the amino group is substituted by one or twobenzyloxycarbonyl-lower alkyl or benzyl radicals which are substitutedby hydroxyl in the phenyl moiety and the other substituents are asdefined above for compounds of the formula I, reacting a compound of theformula I in which the radical R is methoxy or in which one of theradicals R₁ or R₂ is amino-lower alkyl whose amino group is substitutedby one or two benzyloxycarbonyl-lower alkyl or benzyl radicals which aresubstituted by methoxy in the phenyl moiety, and the other substituentsare as defined above for compounds of the formula I, free functionalgroups present in the radicals R, R₁ and R₂ if necessary being protectedby easily removable protective groups, with boron tribromide, andremoving protective groups present, or

d) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is aminomethyl in which the amino group issubstituted by one or two hydroxy-lower alkyl, amino-lower alkyl,carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl,benzyloxycarbonyl-lower alkyl or benzyl radicals which in the phenylmoiety are unsubstituted or substituted by halogen, lower alkyl,hydroxymethyl, aminomethyl, hydroxyl, lower alkanoyloxy, lower alkoxy,carboxyl, lower alkanoyl, benzoyl, lower alkoxycarbonyl, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, cyano, amino, loweralkanoylamino, lower alkylamino, N,N-di-lower alkylamino ortrifluoromethyl, or in which one of the radicals R₁ and R₂ is 4-loweralkylpiperazinomethyl, morpholinomethyl or piperidinomethyl and theother substituents are as defined above for compounds of the formula I,reacting a compound of the formula I in which one of the radicals R₁ andR₂ is formyl and the other substituents are as defined above forcompounds of the formula I, free functional groups present in theradical R if necessary being protected by easily removable protectivegroups, with an amine of the formula VII

HN(R₁₀)R₁₁  (VII)

 in which

α) R₁₀ is hydrogen, hydroxy-lower alkyl, amino-lower alkyl,carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl,benzyloxycarbonyl-lower alkyl or benzyl, the benzyloxycarbonyl-loweralkyl or benzyl radicals in the phenyl moiety being unsubstituted orsubstituted by halogen, lower alkyl, hydroxymethyl, aminomethyl,hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkanoyl,benzoyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylcarbamoyl, cyano, amino, lower alkanoylamino, loweralkylamino, N,N-di-lower alkylamino or trifluoromethyl, and

R₁₁ is hydroxy-lower alkyl, amino-lower alkyl, carboxy-lower alkyl,lower alkoxycarbonyl-lower alkyl, benzyloxycarbonyl-lower alkyl orbenzyl, the benzyl oxycarbonyl-lower alkyl or benzyl radicals in thephenyl moiety being unsubstituted or substituted by halogen, loweralkyl, hydroxymethyl, aminomethyl, hydroxyl, lower alkanoyloxy, loweralkoxy, carboxyl, lower alkanoyl, benzoyl, lower alkoxycarbonyl,carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, cyano,amino, lower alkanoylamino, lower alkylamino, N,N-di-lower alkylamino ortrifluoromethyl, or

β) in which the radicals R₁₀ and R₁₁ together are pentane-1,5-diyl,3-N-lower alkyl-3-azapentane-1,5-diyl or 3-oxapentane-1,5-diyl,

 catalytically hydrogenating the product and then removing protectivegroups present, or

e) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is a radical of the formula —CH═N—OR₉ in which R₉is hydrogen or lower alkyl, and the other substitutents are as definedabove for compounds of the formula I, reacting a compound of the formulaI, in which one of the radicals R₁ and R₂ is formyl and the othersubstituents are as defined above for compounds of the formula I, freefunctional groups present in the radical R if necessary being protectedby easily removable protective groups, with a hydroxylamine derivativeof the formula VIII

H₂N—O—R₁₂  (VIII)

 in which R₁₂ is hydrogen or lower alkyl, and removing protective groupspresent, or

f) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is piperidine-1-carbonyl, piperazine-1-carbonyl,4-lower alkylpiperazine-1-carbonyl or morpholine-4-carbonyl, and theother substituents are as defined above for compounds of the formula I,reacting a compound of the formula I in which one of the radicals R₁ andR₂ is carboxyl and the other substituents are as defined above forcompounds of the formula I, free functional groups present in theradical R if necessary being protected by easily removable protectivegroups, or a reactive carboxylic acid derivative of such a compound,with an amine of the formula VII

HN(R₁₀)R₁₁  (VII)

 in which the radicals R₁₀ and R₁₁ together are pentane-1,5-diyl,3-azapentane-1,3-diyl, 3-N-lower alkyl-3-azapentane-1,3-diyl or3-oxapentane-1,3-diyl, and then removing protective groups present, or

g) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is thiocarbamoyl and the other substituents areas defined above for compounds of the formula I, reacting a compound ofthe formula I in which one of the radicals R₁ and R₂ is aminocarbonyland the other substituents are as defined above for compounds of theformula I, free functional groups present in the radical R if necessarybeing protected by easily removable protective groups, with Lawesson'sreagent, and then removing protective groups present, or

h) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is R₁₃-thiazol-2-yl in which R₁₃ in each case isunsubstituted or substituted lower alkyl or phenyl and the othersubstituents are as defined above for compounds of the formula I,reacting a compound of the formula I in which one of the radicals R₁ andR₂ is thiocarbamoyl and the other substituents are as defined above forcompounds of the formula I, free functional groups present in theradical R if necessary being protected by easily removable protectivegroups, with a compound of the formula IX

 in which X is a leaving group and R₁₃ in each case is unsubstituted orsubstituted lower alkyl or phenyl, free functional groups present in theradical R₁₃ if necessary being protected by easily removable protectivegroups, and then removing protective groups present, or

i) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is tetrazol-5-yl and the other substituents areas defined above for compounds of the formula I, reacting a compound ofthe formula I in which one of the radicals R₁ and R₂ is cyano and theother substituents are as defined above for compounds of the formula I,free functional groups present in the radical R if necessary beingprotected by easily removable protective groups, with a suitable alkalimetal azide, and then removing protective groups present, or

j) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is 2-lower alkyltetrazol-5-yl and the othersubstituents are as defined above for compounds of the formula I,reacting a compound of the formula I in which one of the radicals R₁ andR₂ is tetrazol-5-yl and the other substituents are as defined above forcompounds of the formula I, free functional groups present in theradical R if necessary being protected by easily removable protectivegroups, with the appropriate lower alkyl iodide, and then removingprotective groups present, or

k) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is a radical of the formula II

 in which at least one radical R₄ is lower alkylsulfonylamino,benzenesulfonylamino or toluenesulfonylamino and the other substituentsand symbols are as defined above for compounds of the formula I,reacting a compound of the formula I in which one of the radicals R₁ andR₂ is a radical of the formula II in which at least one radical R₄ isamino and the other substituents and symbols are as defined above forcompounds of the formula I, free functional groups present in theradical R and, if present, the other radicals R₄ if necessary beingprotected by easily removable protective groups, with a compound of theformula X

R₁₄—SO₂—X  (X)

 in which X is chlorine or bromine and R₁₄ is lower alkyl, phenyl or4-methylphenyl, and then removing protective groups present, or

l) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is a radical of the formula II

 in which at least one radical R₄ is a radical of the formula—N═C(R₅)—R₆ in which R₅ is hydrogen and R₆ is as defined above forcompounds of the formula I and the other substituents and symbols are asdefined above for compounds of the formula I, reacting a compound of theformula I in which one of the radicals R₁ and R₂ is a radical of theformula II in which at least one radical R₄ is amino and the othersubstituents and symbols are as defined above for compounds of theformula I, free functional groups present in the radical R and, ifpresent, the other radicals R₄ if necessary being protected by easilyremovable protective groups, with an acetal of the formula XI

 in which R₁₅ and R₁₆ are each individually lower alkyl or togetherpentane-1,5-diyl, 3-N-lower alkyl-3-azapentane-1,5-diyl or3-oxapentane-1,5-diyl, and each R₁₇ is lower alkyl, and then removingprotective groups present, or

m) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is a radical of the formula II

 in which at least one radical R₄ is N³-lower alkylureido orN³-phenylureido and the other substituents and symbols are as definedabove for compounds of the formula I, reacting a compound of the formulaI in which one of the radicals R₁ and R₂ is a radical of the formula IIin which at least one radical R₄ is amino and the other substituents andsymbols are as defined above for compounds of the formula I, freefunctional groups present in the radical R and, if present, the otherradicals R₄ if necessary being protected by easily removable protectivegroups, with an isocyanate of the formula XII

R₁₈—N═C═O  (XII)

 in which R₁₈ is lower alkyl or phenyl, and then removing protectivegroups present, or

n) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is a radical of the formula II

 in which at least one radical R₄ is N³-lower alkylthioureido orN³-phenylthioureido and the other substituents and symbols are asdefined above for compounds of the formula I, reacting a compound of theformula I in which one of the radicals R₁ and R₂ is a radical of theformula II in which at least one radical R₄ is amino and the othersubstituents and symbols are as defined above for compounds of theformula I, free functional groups present in the radical R and, ifpresent, the other radicals R₄ if necessary being protected by easilyremovable protective groups, with an isothiocyanate of the formula XIII

R₁₈—N═C═S  (XIII)

 in which R₁₈ is lower alkyl or phenyl, and then removing protectivegroups present, or

o) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is a radical of the formula II

 in which at least one radical R₄ is lower alkoxycarbonylamino orbenzyloxycarbonyl-amino and the other substituents and symbols are asdefined above for compounds of the formula I, reacting a compound of theformula I in which one of the radicals R₁ and R₂ is a radical of theformula II in which at least one radical R₄ is amino and the othersubstituents and symbols are as defined above for compounds of theformula I, free functional groups present in the radical R and, ifpresent, the other radicals R₄ if necessary being protected by easilyremovable protective groups, with a chloroformic acid ester of theformula XIV

Cl—C(═O)—OR₂₀  (XIV)

 in which R₂₀ is lower alkyl or benzyl, and then removing protectivegroups present,

and after carrying out one of the process variants a) to o), ifnecessary for the preparation of a salt, converting a free compound ofthe formula I obtained into a salt or, if necessary for the preparationof a free compound, converting a salt of a compound of the formula Iobtained into the free compound.

Detailed Description of the Process Steps

The above processes are described in detail below (see also GermanOffenlegungs-schrift No. 30 36 390, published on May 13, 1982, and A.Jorgensen et al., J. Heterocycl. Chem. 22, 859 [1985]). In the moreprecise description that follows, unless otherwise indicated theradicals R, R₁ and R₂ and n are as defined for compounds of the formulaI.

General Points:

The end products of the formula I may contain substituents that can alsobe used as protective groups in starting materials for the preparationof other end products of the formula I. Unless the context indicatesotherwise, the term “protective group” is used in this text to denoteonly an easily removable group that is not a constituent of theparticular desired end product of the formula I.

Process a)

In the compound of the formula IV a suitable leaving group X ispreferably halogen, such as bromine, iodine or especially chlorine.1-Aryl-lower alkyl Z is preferably 1-phenyl-lower alkyl, such asespecially 1-phenylethyl or, in particular, benzyl.

Free functional groups present in the radicals R₁ and R₂, which ifnecessary are protected by easily removable protective groups, areespecially amino or lower alkylamino.

Protective groups and their introduction and removal are described, forexample, in “Protective Groups in Organic Chemistry”, Plenum Press,London, New York 1973, and in “Methoden der organischen Chemie”,Houben-Weyl, 4th edition, Vol. 15/1, Georg-Thieme-Verlag, Stuttgart 1974and in Theodora W. Greene, “Protective Groups in Organic Synthesis”,John Wiley & Sons, New York 1981. It is a characteristic of protectivegroups that they can be removed easily, i.e. without undesired secondaryreactions taking place, for example by solvolysis, reduction, photolysisor alternatively under physiological conditions.

A protected amino group may be present, for example, in the form of aneasily cleavable acylamino, arylmethylamino, etherified mercaptoamino or2-acyl-lower alk-1-enylamino group.

In a corresponding acylamino group, acyl is, for example, the acylradical of an organic carboxylic acid having, for example, up to 18carbon atoms, especially an unsubstituted or substituted, for examplehalo- or aryl-substituted, alkane-carboxylic acid or an unsubstituted orsubstituted, for example halo-, lower alkoxy- or nitro-substituted,benzoic acid, or of a carbonic acid hemiester. Such acyl groups are, forexample, lower alkanoyl, such as formyl, acetyl or propionyl, halo-loweralkanoyl, such as 2-haloacetyl, especially 2-chloro-, 2-bromo-, 2-iodo-,2,2,2-trifluoro- or 2,2,2-trichloro-acetyl, unsubstituted orsubstituted, for example halo-, lower alkoxy- or nitro-substituted,benzoyl, for example benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or4-nitrobenzoyl, or lower alkoxycarbonyl that is branched in the1-position of the lower alkyl radical or suitably substituted in the 1-or 2-position, especially tert-lower alkoxycarbonyl, for exampletert-butoxy-carbonyl, arylmethoxycarbonyl having one or two arylradicals which are preferably phenyl that is unsubstituted or mono- orpoly-substituted, for example, by lower alkyl, especially tert-loweralkyl, such as tert-butyl, lower alkoxy, such as methoxy, hydroxyl,halogen, for example chlorine, and/or by nitro, such as unsubstituted orsubstituted benzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl, orsubstituted diphenylmethoxycarbonyl, for example benzhydryloxycarbonylor di(4-methoxyphenyl)methoxycarbonyl, aroylmethoxycarbonyl in which thearoyl group is preferably benzoyl that is unsubstituted or substituted,for example, by halogen, such as bromine, for examplephenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or2-iodoethoxycarbonyl, or 2-(tri-substituted silyl)ethoxycarbonyl inwhich the substituents are each independently of the others anunsubstituted or substituted, for example lower alkyl-, lower alkoxy-,aryl-, halo- or nitro-substituted, aliphatic, araliphatic,cycloaliphatic or aromatic hydrocarbon radical having up to 15 carbonatoms, such as corresponding, unsubstituted or substituted lower alkyl,phenyl-lower alkyl, cycloalkyl or phenyl, for example 2-tri-loweralkylsilylethoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or2-(di-n-butylmethylsilyl)ethoxycarbonyl, or2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

In an arylmethylamino group, which is a mono-, di- or especiallytri-arylmethyl-amino group, the aryl radicals are especiallyunsubstituted or substituted phenyl radicals. Such groups are, forexample, benzyl-, diphenylmethyl- and especially trityl-amino.

An etherified mercapto group in an amino group protected by such aradical is especially arylthio or aryl-lower alkylthio, in which arylis, especially, phenyl that is unsubstituted or substituted, forexample, by lower alkyl, such as methyl or tert-butyl, lower alkoxy,such as methoxy, halogen, such as chlorine, and/or by nitro. Acorresponding amino protective group is, for example, 4-nitrophenylthio.

In a 2-acyl-lower alk-1-en-1-yl radical that can be used as an aminoprotective group, acyl is, for example, the corresponding radical of alower alkanecarboxylic acid, of a benzoic acid that is unsubstituted orsubstituted, for example, by lower alkyl, such as methyl or tert-butyl,lower alkoxy, such as methoxy, halogen, such as chlorine, and/or bynitro, or especially of a carbonic acid hemiester, such as a carbonicacid lower alkyl hemiester. Corresponding protective groups areespecially 1-lower alkanoylprop-1-en-2-yl, such as1-acetylprop-1-en-2-yl, or 1-lower alkoxycarbonylprop-1-en-2-yl, forexample 1-ethoxycarbonylprop-1-en-2-yl.

Preferred amino protective groups are acyl radicals of carbonic acidhemiesters, especially tert-butyloxycarbonyl, benzyloxycarbonyl that isunsubstituted or substituted, for example as indicated, for example4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-loweralkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, also trityl orformyl.

The reaction between the derivative of the formula IV and the anilinederivative of the formula V takes place in suitable inert polarsolvents, especially alcohols, for example lower alkanols, such asmethanol, propanol, isopropanol or especially ethanol or n-butanol. Insome cases the addition of a solubilizer, such as1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), isadvantageous. The reaction takes place at elevated temperatures, forexample in a temperature range from 70 to 150° C, preferably underreflux conditions.

If Z in the compound of the formula IV is 1-aryl-lower alkyl, thisradical is removed from the resulting precursor of the compound of theformula I (with Z instead of the hydrogen atom on the nitrogen). This iseffected, for example, by treatment with protonic acids, such ashydrochloric acid, phosphoric acids or polyphosphoric acid, at preferredtemperatures from 20° C. to 150° C. and where appropriate in thepresence of water (this is especially the preferred method forZ=1-phenylethyl); or preferably by treatment with Lewis acids,especially AlCl₃, in an aromatic solvent, especially in benzene and/ortoluene, at elevated temperature, especially under reflux [this isespecially the preferred variant for Z=benzyl; see also the analogousprocess in Chem. Pharm. Bull. 39(5), 1152 (1991)].

The removal of the protective groups that are not constituents of thedesired end product of the formula I is effected in a manner known perse, for example by means of solvolysis, especially hydrolysis,alcoholysis or acidolysis, or by means of reduction, especiallyhydrogenolysis or chemical reduction, where appropriate stepwise orsimultaneously.

A protected amino group is liberated in a manner known per se and,according to the nature of the protective groups, in various ways,preferably by solvolysis or reduction. 2-Halo-lower alkoxycarbonylamino(where appropriate after conversion of a 2-bromo-loweralkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylaminogroup), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino canbe cleaved, for example, by treatment with a suitable chemical reducingagent, such as zinc in the presence of a suitable carboxylic acid, suchas aqueous acetic acid. Aroylmethoxycarbonylamino can be cleaved also bytreatment with a nucleophilic, preferably salt-forming, reagent, such assodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also bytreatment with an alkali metal dithionite, for example sodiumdithionite. Unsubstituted or substituted diphenylmethoxycarbonylamino,tert-lower alkoxycarbonylamino or 2-trisubstitutedsilylethoxycarbonylamino can be cleaved by treatment with a suitableacid, for example formic acid or trifluoroacetic acid; unsubstituted orsubstituted benzyloxycarbonylamino can be cleaved, for example, by meansof hydrogenolysis, i.e. by treatment with hydrogen in the presence of asuitable hydrogenation catalyst, such as a palladium catalyst;unsubstituted or substituted triarylmethylamino or formylamino can becleaved, for example, by treatment with an acid, such as a mineral acid,for example hydrochloric acid, or with an organic acid, for exampleformic, acetic or trifluoroacetic acid, where appropriate in thepresence of water; and an amino group protected by an organic silylgroup can be liberated, for example, by means of hydrolysis oralcoholysis. An amino group protected by 2-haloacetyl, for example2-chloroacetyl, can be liberated by treatment with thiourea in thepresence of a base, or with a thiolate salt, such as an alkali metalthiolate, of thiourea, and subsequent solvolysis, such as alcoholysis orhydrolysis, of the resulting condensation product. An amino groupprotected by 2-substituted silylethoxycarbonyl can be converted into thefree amino group also by treatment with a salt of hydrofluoric acid thatyields fluoride anions.

Process b)

1-Aryl-lower alkyl Z′ in a compound of the formula VI is especially1-phenylethyl and also benzyl.

The compound of the formula VI is in tautomeric equilibrium(lactam/lactim form), the lactam form (formula VI) presumablypredominating. Formula VI is used to represent the two possibleequilibrium forms.

The lactim form has the formula VIa

in which the radicals are as defined for compounds of the formula VI.

The present invention also relates to the novel compounds of theformulae VI and VIa.

The dehydrating agent employed especially a strong chemical dehydratingagent, in particular phosphorus pentoxide (P₄O₁₀).

A suitable tertiary amine is primarily ammonia substituted by threeradicals selected independently of one another from alkyl, especiallylower alkyl, such as methyl or ethyl, and cycloalkyl having 3 to 7carbon atoms, especially cyclohexyl, for exampleN,N-dimethyl-N-cyclohexylamine, N-ethyl-N,N-diisopropylamine ortriethylamine, or, furthermore, also pyridine, N-methylmorpholine or4-dimethylaminopyridine.

The reaction between the pyrrolopyrimidinone of the formula VI and theaniline derivative of the formula V takes place at elevated temperature,for example at 200 to 250° C.

Process c)

The reaction is carried out with the exclusion of moisture.

Process d)

The reaction is preferably carried out in a suitable inert solvent, forexample a suitable alcohol, such as especially methanol, in the presenceof 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) and aceticacid at temperatures from approximately +10° C. to +70° C., preferablyat room temperature.

The hydrogenation is carried out at elevated pressure or preferablynormal pressure in the presence of a suitable hydrogenation catalyst,such as especially Raney nickel, in the above reaction solution attemperatures from approximately 10° C. to +70° C., preferably at 50° C.

Process e)

The reaction is preferably carried out in a suitable inert solvent, forexample a suitable alcohol, such as especially methanol, at temperaturesfrom approximately +10° C. to +100° C., preferably at the boilingtemperature of the reaction mixture. In this case the hydroxylaminederivative of the formula VII is preferably employed as a salt andconverted into the free base by addition of an aqueous solution ofsodium acetate to the reaction mixture.

Process f)

A reactive carboxylic acid derivative of a compound of the formula I inwhich one of the radicals R₁ and R₂ is carboxyl and the othersubstituents are as defined above for compounds of the formula I is, forexample, a suitable ester, such as especially an ethyl ester.

Where possible, for example if morpholine is the amine of the formulaVII, the amine of the formula VII can be used itself as a solvent. Inother cases a suitable inert solvent, e.g. dimethylformamide, togetherwith TPTU (O-(1,2-dihydro-2-oxo-1-pyridyl)N,N,N′,N′-tetramethyluroniumtetrafluoroborate is used. The reaction is preferably carried out attemperatures from approximately +10° C. to +150° C., preferably fromroom temperature to 100° C.

Process g)

Lawesson's reagent is2,4-di[4-methoxyphenyl]-1,3-dithia-2,4-diphosphetane-2,4-disulfide andis commercially available, inter alia from SIGMA, FLUKA etc. Thereaction is preferably carried out in a suitable inert solvent, e.g. asuitable ether, such as especially a cyclic ether, e.g. tetrahydrofuran,at temperatures from approximately 50° C. to 150° C., preferably at theboiling temperature of the reaction mixture.

Process h)

R₁₃ is preferably lower alkyl, such as especially ethyl, orunsubstituted or halo-, lower alkyl-, hydroxymethyl-, aminomethyl-,hydroxyl-, lower alkanoyloxy-, lower alkoxy-, carboxyl-, loweralkanoyl-, benzoyl-, lower alkoxycarbonyl-, carbamoyl-, N-loweralkylcarbamoyl-, N,N-di-lower alkylcarbamoyl-, cyano-, amino-, loweralkanoylamino-, lower alkylamino-, N,N-di-lower alkylamino- ortrifluoromethyl-substituted phenyl, in particular 4-methoxyphenyl.

The reaction is preferably carried out in a suitable inert solvent, e.g.a suitable alcohol, such as especially methanol, or a suitable ether,e.g. dioxane, at temperatures from approximately +20° C. to +180° C.,preferably at the boiling temperature of the reaction mixture.

Process i)

The reaction is preferably carried out in a suitable inert solvent, e.g.a suitable alcohol, such as especially 1-methoxyethanol, in the presenceof lithium chloride, e.g. one and a half times the molar amount oflithium chloride, at temperatures from approximately +20° C. to +180°C., preferably at the boiling temperature of the reaction mixture.

Process j)

The reaction is preferably carried out in a suitable inert solvent, e.g.dimethylformamide, in the presence of sodium hydrogen carbonate, attemperatures from approximately 0° C. to +180° C., preferably at roomtemperature. In this case the lower alkyl iodide, such as especiallymethyl iodide, is preferably added as a solution, e.g. 1 M solution, ina suitable ether, such as dioxane.

Process k)

X is preferably chlorine. The reaction is preferably carried out in asuitable inert and anhydrous solvent, e.g. dimethylacetamide, attemperatures from approximately −30° C. to +70° C., preferably at 0° C.

Process l)

R₁₇ is preferably methyl. The reaction is preferably carried out in asuitable inert and anhydrous solvent, e.g. an ether, such astetrahydrofuran, in the presence of triethylamine at temperatures fromapproximately −10° C. to +70° C., preferably at room temperature.

Process m)

The reaction is preferably carried out in a suitable inert and anhydroussolvent, e.g. an ether, such as tetrahydrofuran, advantageously in thepresence of dimethylacetamide at temperatures from approximately 0° C.to +150° C., preferably at the boiling temperature of the reactionmixture.

Process n)

The reaction is preferably carried out in a suitable inert and anhydroussolvent, e.g. an ether, such as tetrahydrofuran, advantageously in thepresence of dimethylacetamide at temperatures from approximately 0° C.to +150° C., preferably at the boiling temperature of the reactionmixture.

Process o)

The reaction is preferably carried out in a suitable inert and anhydroussolvent, e.g. an ether, such as dioxane, advantageously in the presenceof 2,6-lutidine, at temperatures from approximately −30° C. to +150° C.,preferably at room temperature.

Starting Materials:

The starting materials of the formula IV are novel and the presentinvention also relates thereto. They can be prepared by processesanalogous to those described in German Offenlegungsschrift No. 28 18 676(published on Nov. 8, 1979) and German Offenlegungsschrift No. 30 36 390(published on May 13, 1982).

The starting material of the formula IV in which X is chlorine isobtained, for example, from a compound analogous to formula IV in whichX is hydroxyl (see the compounds of the formula VIa) by reaction withphosphorus oxychloride (phosphoryl chloride, P(═O)Cl₃) with theexclusion of moisture at reflux temperature. If desired, the furtherreaction of the starting material of the formula IV thus obtained inwhich X is chlorine can be carried out with an aniline derivative of theformula V in the same vessel, i.e. as a one-pot reaction. For thispurpose, after the reaction with phosphorus oxychloride is complete, thereaction mixture is evaporated to dryness, suspended using a suitablesolvent, such as n-butanol, and reacted further with the anilinederivative of the formula V.

A compound analogous to formula IV in which X is hydroxyl is obtained,for example, from a compound of the formula XV

in which the symbols are as defined above, by reaction with formic acidwhich is preferably employed in excess relative to the compound of theformula XV, for example in a 10 to 30 molar excess, where appropriate inthe presence of inert solvents, such as dimethylformamide, at elevatedtemperature, for example at temperatures from 80° C. to the boilingtemperature.

Alternatively, a compound analogous to formula IV in which X is hydroxyland the other symbols are as defined above is obtained, for example,from a compound of the formula XVI

in which R₁₉ is lower alkyl, such as especially ethyl, and the othersymbols are as defined above, by reaction with a large excess offormamide in a mixture of anhydrous dimethylformamide and formic acid.The reaction is carried out at elevated temperature, for example at from100° C. to 150° C., and preferably under protective gas.

The present invention also relates to the novel starting materials ofthe formulae XV and XVI.

The 1-(Z′)-2-amino-3-cyanopyrroles of the formula XV used asintermediates can be prepared in good yields by methods that are knownper se and have been published [see, for example, Roth, H. J., and Eger,K., Arch. Pharmaz. 308, 179 (1975)]. For this purpose, for example, acompound of the formula XVII

is reacted first with an amine of the formula Z′-NH₂ to give a compoundof the formula XVIII

which is then converted with malononitrile of the formula CH₂(CN)₂ intothe desired intermediate of the formula XV. In detail, the reaction withthe amine Z′-NH₂ is carried out under customary condensation conditions,for example in the presence of catalytic amounts of a strong acid, forexample hydrochloric acid or p-toluenesulfonic acid, at elevatedtemperature (preferably at boiling heat) in a suitable solvent, forexample benzene or toluene, with separation of water, to give therespective α-amino ketone of the formula XVIII. The latter is notisolated but is immediately condensed with malononitrile with heatingand with further separation of water, if necessary with the addition ofa small amount of a base, such as piperidine, a compound of the formulaXV being obtained.

The compounds of the formula XVI used as intermediates are obtained, forexample, by reacting a 2-amidinoacetic acid lower alkyl ester of theformula XIX

wherein R₁₉ is as defined above, with a 2-X-1-R₂-ethan-1-one derivativeof the formula XX

in which the symbols are as defined above. The leaving group X ispreferably bromine. The 2-amidinoacetic acid lower alkyl ester of theformula XIX is liberated from its acid addition salt, such as especiallyits hydrochloride, before the start of the reaction with the aid ofequinormal amounts of a base, such as especially sodium ethoxide, withice-cooling. The reaction is carried out in a suitable solvent, such asespecially a lower alkanol, such as preferably ethanol, at preferredtemperatures of from 0° C. to 50° C., especially at room temperature.

A starting compound of the formula I in which one of the radicals R₁ andR₂ is formyl, carboxyl, lower alkoxycarbonyl, cyano, carbamoyl,thiocarbamoyl, aminophenyl or tetrazol-5-yl and the other substituentsare as defined above for compounds of the formula I, free functionalgroups present in the radical R if necessary being protected by easilyremovable protective groups, are obtained as explained in an exemplarymanner in the examples section. A person skilled in the art can transferthe specific exemplified reactions without major effort to compoundshaving other radicals R and R₁ or R₂ than those which are specificallyexemplified, provided that free functional groups present in the radicalR are protected by easily removable protective groups, if necessary,that is if these interfere with the desired reaction. In many cases,especially if, for example, R is halogen, no protection is necessary.

General Process Conditions:

Free compounds of the formula I having salt-forming properties that areobtainable according to the process can be converted into their salts ina manner known per se, for example by treating with acids or suitablederivatives thereof, for example by addition of the appropriate acid tothe compound of the formula I dissolved in a suitable solvent, forexample an ether, such as a cyclic ether, especially dioxane or inparticular tetrahydrofuran.

Mixtures of isomers obtainable according to the invention can beseparated into the individual isomers in a manner known per se;racemates can be separated, for example, by forming salts with opticallypure salt-forming reagents and separating the mixture of diastereomersthus obtainable, for example by means of fractional crystallization.

The reactions described above can be carried out under reactionconditions known per se, in the absence or, customarily, the presence ofsolvents or diluents, preferably those that are inert towards thereagents used and are solvents therefor, in the absence or presence ofcatalysts, condensing agents (for example phosphorus pentoxide) orneutralizing agents, for example bases, especially nitrogen bases, suchas triethylamine hydrochloride, depending on the nature of the reactionand/or of the reactants at reduced, normal or elevated temperature, forexample in a temperature range from approximately −80° C. toapproximately 200° C., preferably from approximately −20° C. toapproximately 150° C., for example at the boiling point of the solventused, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder a nitrogen atmosphere.

The specific reaction conditions given in each case are preferred.

Solvents and diluents are, for example, water, alcohols, for examplelower alkyl hydroxides, such as methanol, ethanol, propanol orespecially butanol, diols, such as ethylene glycol, triols, such asglycerol, or aryl alcohols, such as phenol, acid amides, for examplecarboxylic acid amides, such as dimethylformamide, dimethylacetamide or1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), carboxylicacids, especially formic acid or acetic acid, amides of inorganic acids,such as hexamethylphosphoric acid triamide, ethers, for example cyclicethers, such as tetrahydrofuran or dioxane, or acyclic ethers, such asdiethyl ether or ethylene glycol dimethyl ether, halogenatedhydrocarbons, such as halo-lower alkanes, for example methylene chlorideor chloroform, ketones, such as acetone, nitrites, such as acetonitrile,acid anhydrides, such as acetic anhydride, esters, such as ethylacetate, bis-alkanesulfines, such as dimethyl sulfoxide,nitrogen-containing heterocyclic compounds, such as pyridine,hydrocarbons, for example lower alkanes, such as heptane, or aromaticcompounds, such as benzene, toluene or xylene(s), or mixtures of thesesolvents, it being possible for the solvents suitable in each case forthe abovementioned reactions to be selected.

Customary processes are used for working up the obtainable compounds ofthe formula I or their salts, for example solvolysis of excess reagents;recrystallizing; chromatographing, for example partition, ion or gelchromatography; partitioning between inorganic and organic solventphases; single or multiple extraction, especially after acidifying orincreasing the basicity or the salt content; drying over hygroscopicsalts; digesting; filtering; washing; dissolving; evaporating (ifnecessary in vacuo or under a high vacuum); distillation;crystallization, for example of compounds obtained in oil form or fromthe mother liquor, seeding with a crystal of the end product also beingpossible; or a combination of two or more of the working-up stepsmentioned, which can also be employed repeatedly, etc.

Starting materials and intermediates can be used in pure form, forexample after working-up, as just mentioned, in partly purified form oralternatively, for example, directly as a crude product.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may include, for example, the solventused for crystallization. The present invention also relates to thesehydrates or solvates of the compounds of the formula I, and to thestarting materials described as belonging to the subject matter of theinvention.

In view of th e close relationship between the compounds of the formulaI in free form and in the form of their salts, hereinabove andhereinbelow the free compounds and their salts are to be understood asmeaning also the corresponding salts and free compounds, respectively,as appropriate and expedient, provided that the compounds containsalt-forming groups. The same applies to the hydrates and solvates.

In the process of the present invention, the starting materials employedare preferably those that lead to the novel compounds of the formula Idescribed at the beginning as being especially valuable.

The invention also relates to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as a starting material and the remaining process steps are carriedout or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example a saltthereof.

Pharmaceutical Compositions, their Preparation and the Use According tothe Invention of the Compounds of the Formula I and of CompositionsComprising these Compounds as Active Ingredient

The present invention also relates to pharmaceutical compositions thatcomprise one of the compounds of the formula I as active ingredient andthat can be used especially for the treatment of the diseases mentionedearlier. Compositions for enteral administration, such as nasal, buccal,rectal or, especially, oral administration, and for parenteraladministration, such as intravenous, intramuscular or subcutaneousadministration, to warm-blooded animals, especially humans, areespecially preferred. The compositions comprise the active ingredient onits own or, preferably, together with a pharmaceutically acceptablecarrier. The dosage of the active ingredient depends upon the disease tobe treated and upon the species, its age, weight and individualcondition, the individual pharmacokinetic data, the disease to betreated and also upon the mode of administration.

The invention also relates to pharmaceutical compositions for use in amethod for the therapeutic treatment of the human or animal body, to aprocess for the preparation thereof (especially as compositions for thetreatment of tumors) and to a method of treating neoplastic diseases,especially those mentioned above.

A pharmaceutical composition is preferred which is suitable foradministration to a warm-blooded animal, especially a human, sufferingfrom a disease that is responsive to inhibition of a protein kinase, forexample psoriasis or a tumor, comprising a compound of the formula I, ora salt thereof if salt-forming groups are present, in an amounteffective for the inhibition of the protein kinase, together with atleast one pharmaceutically acceptable carrier.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95% of the active ingredient, administration forms insingle dose form preferably comprising from approximately 20% toapproximately 90% of active ingredient and administration forms that arenot in single dose form preferably comprising from approximately 5% toapproximately 20% of active ingredient. Unit dose forms are, forexample, sugar-coated tablets, tablets, ampoules, vials, suppositoriesor capsules. Other administration forms are, for example, ointments,creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions,etc. Examples are capsules, comprising from approximately 0.05 g toapproximately 1.0 g of the active ingredient.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional mixing,granulating, sugar-coating, dissolving or lyophilizing processes.

Solutions of the active ingredient are preferably used, and alsosuspensions or dispersions, to be precise especially isotonic aqueoussolutions, dispersions or suspensions which, for example in the case oflyophilized compositions which comprise the active ingredient on its ownor together with a carrier, for example mannitol, can be prepared beforeuse. The pharmaceutical compositions may be sterilized and/or maycomprise excipients, for example preservatives, stabilizers, wettingagents and/or emulsifiers, solubilizers, salts for regulating theosmotic pressure and/or buffers, and are prepared in a manner known perse, for example by means of conventional dissolving and lyophilizingprocesses. The solutions or suspensions mentioned may compriseviscosity-increasing substances, such as sodium carboxymethylcellulose,carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil comprise as the oil component the vegetable,synthetic or semi-synthetic oils customary for injection purposes. Theremay be mentioned as such especially liquid fatty acid esters thatcontain as the acid component a long-chain fatty acid having 8-22,especially 12-22, carbon atoms, for example lauric acid, tridecylicacid, myristic acid, pentadecylic acid, palmitic acid, margaric acid,stearic acid, arachidic acid, behenic acid or corresponding unsaturatedacids, for example oleic acid, elaidic acid, erucic acid, brassidic acidor linoleic acid, if desired with the addition of antioxidants, forexample vitamin E, β-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. Thealcohol component of these fatty acid esters has a maximum of 6 carbonatoms and is a mono- or polyhydric, for example a mono-, di- ortrihydric alcohol, for example methanol, ethanol, propanol, butanol orpentanol or their isomers, but especially glycol and glycerol. Thefollowing examples of fatty acid esters are therefore to be mentioned:ethyl oleate, isopropyl myristate, isopropyl palmitate, “Labrafil M2375” (polyoxyethylene glycerol trioleate, Gattefoss{acute over (e)},Paris), “Labrafil M 1944 CS” (unsaturated polyglycolized glyceridesprepared by alcoholysis of apricot kernel oil and consisting ofglycerides and polyethylene glycol ester, Gattefoss{acute over (e)},France), “Labrasol” (saturated polyglycolized glycerides prepared byalcoholysis of TCM and consisting of glycerides and polyethylene glycolester, Gattefoss{acute over (e)}, France) and/or “Miglyol 812”(triglyceride of saturated fatty acids with a chain length of C₈ to C₁₂,H{umlaut over (u)}ls AG, Germany), but especially vegetable oils, suchas cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soyabean oil and in particular groundnut oil.

The injection compositions are prepared in a customary manner understerile conditions; the same applies also to dispensing the compositionsinto ampoules or vials, for example, and sealing the containers.

Pharmaceutical compositions for oral administration can be obtained, forexample, by combining the active ingredient with one or more solidcarriers, where appropriate granulating a mixture obtained, and, ifdesired, processing the mixture or granules, where appropriate byaddition of additional excipients, to give tablets or sugar-coatedtablet cores.

Suitable carriers are especially fillers, such as sugars, for examplelactose, sucrose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tricalcium phosphate or calciumhydrogenphosphate, and also binders, such as starches, for example corn,wheat, rice or potato starch, methylcellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone, and/or, if desired, disintegrators, such as theabovementioned starches, also carboxymethyl starch, crosslinkedpolyvinylpyrrolidone, alginic acid or a salt thereof, such as sodiumalginate. Additional adjuncts are primarily flow conditioners andlubricants, for example silicic acid, talc, stearic acid or saltsthereof, such as magnesium or calcium stearate, and/or polyethyleneglycol, or derivatives thereof.

Sugar-coated tablet cores can be provided with suitable, optionallyenteric, coatings, using, inter alia, concentrated sugar solutions whichmay comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycoland/or titanium dioxide, or coating solutions in suitable organicsolvents or solvent mixtures, or, for the preparation of entericcoatings, solutions of suitable cellulose preparations, such asacetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.Dyes or pigments may be added to the tablets or sugar-coated tabletcoatings, for example for identification purposes or to indicatedifferent doses of active ingredient.

Orally administrable pharmaceutical compositions also include dry-filledcapsules consisting of gelatin, and also soft, sealed capsulesconsisting of gelatin and a plasticizer, such as glycerol or sorbitol.The dry-filled capsules may contain the active ingredient in the form ofgranules, for example as a mixture with fillers, such as corn starch,binders and/or glidants, such as talc or magnesium stearate, and, whereappropriate, stabilizers. In soft capsules, the active ingredient ispreferably dissolved or suspended in suitable liquid excipients, such asfatty oils, paraffin oil or liquid polyethylene glycols or fatty acidesters of ethylene or propylene glycol, to which stabilizers anddetergents, for example of the polyoxyethylene sorbitan fatty acid estertype, may also be added.

Other oral administration forms are, for example, syrups prepared incustomary manner which comprise the active ingredient, for example insuspended form and in a concentration of about 5% to 20%, preferablyabout 10%, or in a similar concentration that provides a suitable singledose, for example, when administered in measures of 5 or 10 ml. Alsosuitable are, for example, powdered or liquid concentrates for thepreparation of shakes, for example in milk. Such concentrates may alsobe packaged in single dose quantities.

Suitable rectally administrable pharmaceutical compositions are, forexample, suppositories that consist of a combination of the activeingredient and a suppository base. Suitable suppository bases are, forexample, natural or synthetic triglycerides, paraffin hydrocarbons,polyethylene glycols or higher alkanols.

For parenteral administration there are primarily suitable aqueoussolutions of an active ingredient in water-soluble form, for example inthe form of a water-soluble salt, or aqueous injection suspensions thatcontain viscosity-increasing substances, for example sodiumcarboxymethylcellulose, sorbitol and/or dextran, and, if desired,stabilizers. The active ingredient, where appropriate together withadjuncts, can also be in the form of a lyophilizate and can be made intoa solution prior to parenteral administration by addition of suitablesolvents.

Solutions such as are used, for example, for parenteral administrationcan also be employed as infusion solutions.

Preferred preservatives are, for example, antioxidants, such as ascorbicacid, or microbicides, such as sorbic acid or benzoic acid.

Ointments are oil-in-water emulsions that contain up to 70%, butpreferably 20%-50%, of water or aqueous phase. Suitable as fatty phaseare primarily hydrocarbons, for example petroleum jelly, paraffin oil orhard paraffins, which, in order to improve the water-binding capacity,preferably contain suitable hydroxy compounds, such as fatty alcohols oresters thereof, for example cetyl alcohol or wool wax alcohols, such aswool wax. Emulsifiers are appropriate lipophilic substances, such assorbitan fatty acid esters (Spans), for example sorbitan oleate and/orsorbitan isostearate. Additives to the aqueous phase are, for example,humectants, such as polyalcohols, for example glycerol, propyleneglycol, sorbitol and/or polyethylene glycol, and also preservatives andperfumes.

Fatty ointments are anhydrous and contain as base especiallyhydrocarbons, for example paraffin, petroleum jelly or paraffin oil,also natural or partially synthetic fats, for example coconut fatty acidtriglyceride, or preferably hardened oils, for example hydrogenatedgroundnut oil or castor oil, also fatty acid partial esters of glycerol,for example glycerol mono- and/or distearate, and also, for example, thefatty alcohols increasing the water-absorption, emulsifiers and/oradditives mentioned in connection with the ointments.

Creams are oil-in-water emulsions that contain more than 50% of water.As oily base there are used primarily fatty alcohols, for examplelauryl, cetyl or stearyl alcohol, fatty acids, for example palmitic orstearic acid, liquid to solid waxes, for example isopropyl myristate,wool wax or beeswax, and/or hydrocarbons, for example petroleum jelly(petrolatum) or paraffin oil. Suitable emulsifiers are surface-activesubstances having predominantly hydrophilic properties, such asappropriate non-ionic emulsifiers, for example fatty acid esters ofpolyalcohols or ethylene oxide adducts thereof, such as polyglycerolfatty acid esters or polyoxyethylene sorbitan fatty acid esters(Tweens), and also polyoxyethylene fatty alcohol ethers or fatty acidesters, or appropriate ionic emulsifiers, such as alkali metal salts offatty alcohol sulfates, for example sodium lauryl sulfate, sodium cetylsulfate or sodium stearyl sulfate, which are customarily used in thepresence of fatty alcohols, for example cetyl alcohol or stearylalcohol. Additives to the aqueous phase are, inter alia, agents thatreduce the drying out of the creams, for example polyalcohols, such asglycerol, sorbitol, propylene glycol and/or polyethylene glycols, andalso preservatives and perfumes.

Pastes are creams and ointments having secretion-absorbing powderconstituents, such as metal oxides, for example titanium oxide or zincoxide, also talc and/or aluminum silicates, the object of which is tobind moisture or secretions present.

Foams are administered from pressurized containers and are liquidoil-in-water emulsions in aerosol form; halogenated hydrocarbons, suchas chlorofluoro-lower alkanes, for example dichlorodifluoromethane anddichlorotetrafluoroethane, or preferably non-halogenated gaseoushydrocarbons, air, N₂O or carbon dioxide, are used as propellant gases.As oil phase there are used, inter alia, those used above in the case ofointments and creams, and also the additives mentioned in thatconnection.

Tinctures and solutions usually have an aqueous-ethanolic base to whichthere are added, inter alia, polyalcohols, for example glycerol, glycolsand/or polyethylene glycol, as humectants for reducing evaporation, andfat-restoring substances, such as fatty acid esters with low molecularweight polyethylene glycols, i.e. lipophilic substances that are solublein the aqueous mixture, as a replacement for the fatty substancesextracted from the skin by the ethanol, and, if necessary, otheradjuncts and additives.

The invention also relates to a process or a method of treating theabovementioned pathological conditions, especially those conditionsresponsive to inhibition of protein kinases. The compounds of theformula I can be administered as such or in the form of pharmaceuticalcompositions, prophylactically or therapeutically, preferably in anamount effective against the diseases mentioned, to a warm-bloodedanimal, for example a human, requiring such treatment, the compoundsespecially being used in the form of pharmaceutical compositions. In thecase of a body weight of about 70 kg a daily dose of approximately 0.1 gto approximately 5 g, preferably from approximately 0.5 g toapproximately 2 g, of a compound of the present invention isadministered.

The following Examples serve to illustrate the invention.

If not mentioned otherwise, the ratio of solvents to one another isgiven in parts by volume (v/v).

The short forms and abbreviations used have the following definitions:

Eluents (gradients):

HPLC gradients:

Grad₂₀ 20%→100% a) in b) for 20 min.

Eluent a): acetonitrile+0.05% TFA; eluent b): water+0.05% TFA. Column(250×4.6 mm) packed with reversed-phase material C₁₈-Nucleosil® (5 μmaverage particle size, silica gel covalently derivatized withoctadecylsilanes, Macherey & Nagel, D{umlaut over (u)}ren, Germany).Detection by UV absorption at 254 nm. The retention times (t_(Ret)) aregiven in minutes.

Flow rate: 1 ml/min.

Abbreviations

abs. absolute (anhydrous) TLC-R_(f) R_(f) according to thin-layerchromatography DEPC diethyl pyrocarbonate DIPE diisopropyl ether DMAdimethylacetamide DMF dimethylformamide DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMSO dimethylsulfoxide El-MS electron impact ionization mass spectroscopy FAB-MS fastatom bombardment mass spectroscopy satd saturated h hour(s) HPLChigh-pressure liquid chromatography HV high vacuum min minute(s) MS massspectroscopy RT room temperature RE rotary evaporator m.p. melting pointbrine saturated sodium chloride solution TFA trifluoroacetic acid THFtetrahydrofuran TPTU O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate

Abbreviations used in NMR Spectra Data

b broad d doublet J coupling constant m multiplet q quartet s singlet ttriplet

EXAMPLE 1

136.4 mg (0.50 mmol) of 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine and 67 μl of N-methylpiperazine in 5 ml of methanol, 15 ml ofDMPU and 63 μl of acetic acid are hydrogenated at 50° C. in the presenceof 30 mg of Raney nickel. The catalyst is filtered off, the filtrate isevaporated and the residue is dissolved in ethyl acetate and satd NaHCO₃solution. The aqueous phase separated off is extracted twice with ethylacetate; the organic phases are washed with satd NaHCO₃ solution, 4times with water and brine, dried over Na₂SO₄ and evaporated. Columnchromatography (SiO₂, CH₂Cl₂/methanol=7:2) and stirring in diethyl etheryields4-(3-chloroanilino)-6-[(4-methylpiperazin-1-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidine;HPLC: t_(Ret)(Grad₂₀)=7.4; TLC-R_(f)=0.16 (CH₂Cl₂/methanol=7:3); FAB-MS:(M+H)⁺=357.

The starting material is obtained as follows:

Stage 1.1: At 0-5° C., 56.0 g (0.43 mol) of ethyl 2-amidinoacetate [forpreparation see: Liebigs Ann. Chem., 1561 (1981)] are initiallyintroduced into 172 ml of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. 56.0 ml (0.45 mol)of ethyl bromopyruvate are added dropwise in the course of 30 min andthe mixture is then warmed to 60° C. for 3 h. The dark-brown reactionsolution is poured onto 1 liter of ice water and extracted with 1 literof ethyl acetate and twice with 0.5 liter of ethyl acetate each time.The organic phases are washed 3 times with 0.5 liter of water and 0.5liter of brine, dried (Na₂SO₄) and evaporated. Column chromatography(SiO₂, hexane/ethyl acetate [1:1]) and crystallization from diethylether-hexane yields 2-amino-3,5-bis(ethoxycarbonyl)-1H-pyrrole; m.p.147-149° C.; MS: (M)⁺=226.

Stage 1.2: With the exclusion of air, 51.5 g (227 mmol) of2-amino-3,5-bis(ethoxycarbonyl)-1H-pyrrole, 455 mmol of formamide, 227ml of DMF and 113 ml of formic acid are stirred at 140° C. for 27 h. Theresulting yellow suspension is cooled to 0-5° C. Filtering and washingwith isopropanol and hexane leads to6-ethoxycarbonyl-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine; ¹H-NMR(DMSO-d₆): 13-12 (2 HX), 7.99 and 7.11 (2s, 2H), 4.31 (q, J=7, 2H), 1.32(t, J=7, 3H).

Stage 1.3: Under a N₂ atmosphere, 32.0 g (154 mmol) of6-ethoxycarbonyl-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine are suspended in308 ml (338 mmol) of POCl₃ at RT and warmed to 120° C. with stirring;the solid dissolves in the course of this. After stirring at 120° C. for3 h, the excess POCl₃ is distilled off (65° C. external temperature; 15mbar). Suspension of the residue in 50 ml of ice-cold toluene,filtration and washing with toluene yields4-chloro-6-ethoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine; m.p. 219-221° C.;¹H-NMR (DMSO-d₆) 8.77 and 7.24 (2s, 2H), 4.39 (q, J=7, 2H), 1.36 (t,J=7, 3H). Further product can be obtained from the evaporated filtrateby stirring in ethyl acetate/water.

Stage 1.4: Under a argon atmosphere, 29.0 g (128 mmol) of4-chloro-6-ethoxy-carbonyl-7H-pyrrolo[2,3-d]pyrimidine and 18.0 ml (171mmol) of 3-chloroaniline in 430 ml of n-butanol are stirred at 100° C.for 3 h (almost dissolved after≈1 h, then a thick suspension is formed).400 ml of isopropanol/hexane (1:1) are then added to the reactionmixture cooled to≈50° C., and the product is filtered off and washedwith isopropanol and hexane. Stirring in diethyl ether yields4-(3-chloroanilino)-6-ethoxy-carbonyl-7H-pyrrolo[2,3-d]pyrimidine;¹H-NMR (DMSO-d₆) 13.0 and 10.53 (2 sb, 2HN), 8.48 (s, 1H), 8.13 (m, 1H),7.78 (dm, J=8, 1H), 7.76 (s, 1H), 7.45 (t, J=8, 1H), 7.21 (dm, J=8),1H), 4.37 (q, J=7, 2H), 1.37 (t, J=7, 3H).

Stage 1.5: Under a N₂ atmosphere, 1.4 g (37 mmol) of lithium aluminumhydride are added in portions to 5.70 g (18 mmol) of4-(3-chloroanilino)-6-ethoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine. Afterstirring at 50° C. for 2 h, 100 ml of water are added dropwise to thereaction mixture and it is filtered through Celite. Water is added tothe filtrate and the mixture is extracted 3 times with ethyl acetate.The organic phases are washed 3 times with water and brine, dried(MgSO₄) and evaporated. Recrystallization from isopropanol yields4-(3-chloroanilino)-6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidine; HPLC:t_(Ret)(Grad₂₀)=8.2; TLC-R_(f)=0.11 (CH₂Cl₂/methanol [10:1]); MS:(M)⁺=274.

Stage 1.6: With ice-cooling, 1.9 g of manganese dioxide (85%) are addedto a suspension of 715 mg (2.6 mmol) of4-(3-chloroanilino)-6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidine in 170ml of methylene chloride and the mixture is stirred at RT for 20 h. 20ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) are thenadded to the reaction mixture, and it is stirred for 1 h and thenfiltered through Hyflo. The filtration residue is again stirred (1 h) in50 ml of methylene chloride/DMPU (1:1) and again filtered. The twofiltrates are combined, evaporated and taken up in ethyl acetate/THF andwater. The aqueous phases are extracted twice with ethyl acetate; theorganic phases are washed 4 times with water and brine, dried (MgSO₄)and evaporated down to a residual volume of ≈20 ml. Addition of diethylether and filtration yields4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine; HPLC:t_(Ret)(Grad₂₀)=10.1; TLC-R_(f)=0.24 (CH₂Cl₂/methanol [10:1]).

EXAMPLE 2

109 mg (0.40 mmol) of4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine (stage 1.6) and70 μl (0.8 mmol) of morpholine in 6 ml of methanol, 2 ml of DMPU and 50μl of acetic acid are heated at 50° C. for 2 h. 30 mg of Raney nickelare then added and the mixture is hydrogenated at 50° C. The catalyst isfiltered off, the filtrate is evaporated and the residue is dissolved inethyl acetate and satd Na₂CO₃ solution. The aqueous phase separated offis extracted twice with ethyl acetate; the organic phases are washedwith satd NaHCO₃ solution, twice with water and brine, dried (MgSO₄) andevaporated. The residue is taken up in methanol, and the solution istreated with silica gel and dried. The powder is added to a silica gelcolumn and eluted with CH₂Cl2/methanol=10:1. Crystallization from ethylacetate/diethyl ether/hexane yields4-(3-chloroanilino)-6-[(morpholin-4-yl)-methyl]-7H-pyrrolo[2,3-d]pyrimidine;m.p: 244-246° C.; HPLC: t_(Ret)(Grad₂₀)=7.4; TLC-R_(f)=0.20(CH₂Cl₂/methanol 10:1); FAB-MS: (M+H)⁺=344.

EXAMPLE 3

109 mg (0.40 mmol) of4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine (stage 1.6) and84 mg (0.8 mmol) of diethanolamine in 6 ml of ethanol, 60 drops of DMPUand 50 μl of acetic acid are stirred at RT for a few hours. 30 mg ofRaney nickel are then added and the mixture is hydrogenated at 50° C.The catalyst is filtered off and the filtrate is evaporated. Columnchromatography (SiO₂, CH₂Cl₂/methanol=10:1) and crystallization fromethyl acetate/diethyl ether yields4-(3-chloroanilino)-6-[bis(2-hydroxyethyl)aminomethyl]-7H-pyrrolo[2,3-d]pyrimidine;HPLC: t_(Ret)(Grad₂₀)=7.0; TLC-R_(f)=0.1 (CH₂Cl₂/methanol=10:1); FAB-MS:(M+H)⁺=362.

EXAMPLE 4

273 mg (1.00 mmol) of4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine (stage 1.6) and156 ml (1.2 mmol) of 4-methoxybenzylamine in 10 ml of methanol, DMPU and126 μl (2.2 mmol) of acetic acid are stirred at RT for 1 h. 0.1 g ofRaney nickel is then added and the mixture is hydrogenated at RT andfinally at 50° C. The catalyst is filtered off, the filtrate isevaporated and the residue is dissolved in ethyl acetate and satd Na₂CO₃solution. The aqueous phase separated off is extracted twice with ethylacetate; the organic phases are washed with satd NaHCO₃ solution, andtwice with water and brine, dried (MgSO₄) and evaporated. Stirring theresidue in diethyl ether yields4-(3-chloroanilino)-6-[(4-methoxybenzylamino)-methyl]-7H-pyrrolo[2,3-d]pyrimidine;HPLC: t_(Ret)(Grad₂₀)=9.5; TLC-R_(f)=0.17 (CH₂Cl₂/methanol=10:1);FAB-MS: (M+H)⁺=394.

EXAMPLE 5

Under an N₂ atmosphere, 29 μl (0.3 mmol) of boron tribromide in 2 ml ofmethylene chloride are added to an ice-cooled suspension of 98.5 mg(0.25 mmol) of4-(3-chloroanilino)-6-[(4-methoxy-benzylamino)-methyl]-7H-pyrrolol[2,3-d]pyrimidine(see Example 4) in 5 ml of abs. methylene chloride. After 3 h, a further60 μl of boron tribromide are added and the mixture is stirred at RTovernight. The reaction mixture is poured onto ice water and extracted 3times with ethyl acetate. The organic phases are washed with satd NaHCO₃solution, twice with water and brine, dried (MgSO₄) and evaporated.Stirring in hot isopropanol affords4-(3-chloroanilino)-6-[(4-hydroxy-benzylamino)methyl]-7H-pyrrolo[2,3-d]pyrimidine;HPLC: t_(Ret)(Grad₂₀)=8.4; FAB-MS: (M+H)⁺=380.

EXAMPLE 6

115 mg (1.66 mmol) of hydroxylammonium chloride and 139 mg (1.69 mmol)of sodium acetate in 2 ml of water are added to 273 mg (1.00 mmol) of4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine (stage1.6) in 3ml of methanol. The suspension is heated to boiling for 3 h, cooled andfiltered, and the residue is washed with water/isopropanol=1:1. Thecrude product is dissolved in about 80 ml of hot THF and clarified withactive carbon. 10 ml of isopropanol are added to the filtrate and it ispartially evaporated. The crystals formed in this process are filteredoff and washed with DIPE and hexane, whereupon pure(E)-4-(3-chloroanilino)-7H-pyrrolo-[2,3-d]pyrimidine-6-carbaldehydeoxime is obtained; ¹H-NMR (DMSO-d₆): 12.16 and 11.35 (2s, 2HN), 9.60 (s,1H), 8.35 (s, 1H), 8.19 (sb, 1H), 8.17 (s, 1H), 7.79 (db, J=8, 1H), 7.35(t, J=8, 1H), 7.05 (db, J=8, 1H), 7.03 (s, 1H); HPLC:t_(Ret)(Grad₂₀)=9.5; FAB-MS: (M+H)⁼288.

After addition of diethyl ether and allowing to stand at −20° C.,(Z)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde oximecrystallizes from the evaporated mother liquor as a mixture with ≈10% ofthe (E) isomer: ¹H-NMR (DMSO-d₆): 12.00 (s, 2HN), 9.71 (s, 1H), 8.39 (s,1H), 8.24 (sb, 1H), 7.84 (db, J=8, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 7.35(t, J=8, 1H), 7.05 (db, J=8, 1H); HPLC: t_(Ret)(Grad₂₀)=9.1; FAB-MS:(M+H)⁺=288.

EXAMPLE 7

69.3 mg (0.83 mmol) of O-methylhydroxylamine hydrochloride and 69.3 mg(0.845 mmol) of sodium acetate in 1 ml of water are added to 163.3 mg(0.5 mmol) of 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine(stage1.6) in 1 ml of methanol. The suspension is heated to boiling for4 h, cooled and filtered, and the residue is washed withwater/isopropanol and finally diethyl ether.4-(3-Chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde O-methyloxime is obtained; HPLC: t_(Ret)(Grad₂₀)=11.3; TLC-R_(f)=0.31(CH₂Cl₂/methanol 10:1) FAB-MS: (M+H)⁺=302.

EXAMPLE 8

168.5 mg (0.53 mmol) of4-(3-chloroanilino)-6-ethoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine(stage1.4) in 3 ml of morpholine are stirred at 50° C. for 5 days and at100° C. for 1 day. Silica gel is added to the reaction mixture, it isevaporated, and the resulting powder is applied to a silica gel columnand eluted with ethanol/methylene chloride 1:15. Stirring the reactionproduct in isopropanol leads to4-(3-chloroanilino)-6-(morpholin-4-yl-carbonyl)-7H-pyrrolo[2,3-d]pyrimidine;HPLC: t_(Ret)(Grad₂₀)=9.2; TLC-R_(f)=0.56 (CH₂Cl₂/methanol=10:1); MS:(M)⁺=357.

EXAMPLE 9

98 mg (0.33 mmol) of TPTU, followed by 133 μl (1.2 mmol) ofN-methyl-piperazine in 1 ml of DMF (→solution) are added to a suspensionof 97.6 mg (0.30 mmol) of6-carboxy-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine in 7 ml ofDMF. After 1 h, a further 30 mg of TPTU are added and the mixture isstirred overnight at RT. The reaction mixture is evaporated in a HV, andthe residue is treated with ethanol/methylene chloride (1:2) and finallywith about 4 ml of ethanol/water (3:1).4-(3-chloroanilino)-6-[(4-methylpiperazin-1-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidinecrystallizes in this process and is filtered off and washed withethanol/water (1:1) and isopropanol/hexane (1:1); m.p. 276-278° C.;HPLC: t_(Ret)(Grad₂₀)=7.3; TLC-R_(f)=0.21 (CH₂Cl₂/ethanol=2:1); MS:(M)⁺=370.

The starting material is obtained as follows:

Step 9.1: A solution of 25 mg (0.6 mmol) of LiOH.H₂O in 0.4 ml of H₂O isadded dropwise to a suspension of 95 mg (0.30 mmol) of4-(3-chloroanilino)-6-ethoxy-carbonyl-7H-pyrrolo[2,3-d]pyrimidine (seestage1.4) in 0.7 ml of methanol and the mixture is heated to boiling for4.5 h. It is cooled in an ice bath and acidified with 0.6 ml of 1 normalHCl solution. Filtering off and washing with water yields6-carboxy-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine; HPLC:t_(Ret)(Grad₂₀)=8.7; FAB-MS: (M+H)⁺=289.

EXAMPLE 10

144 mg (0.50 mmol) of6-aminocarbonyl-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine and 202mg (0.5 mmol) of Lawesson's reagent in 5 ml of THF are heated to boilingfor 17 h and the mixture is then evaporated. Column chromatography(SiO₂, CH₂Cl₂/ethanol=15:1) of the residue and stirring in diethyl etheryields4-(3-chloroanilino)-6-(thiocarbamoyl)-7H-pyrrolo[2,3-d]pyrimidine; HPLC:t_(Ret)(Grad₂₀)=9.8; TLC-R_(f)=0.44 (CH₂Cl₂/methanol=10:1); FAB-MS:(M+H)⁺=304; IR: (KBr) inter alia 1614s, 1566s, 1506m, 1474s, 1380m,1354m, 1294m, 1134m.

The starting material is obtained as follows:

Stage 10.1: 90 mg (0.285 mmol) of4-(3-chloroanilino)-6-ethoxycarbonyl-7H-pyrrolo-[2,3-d]pyrimidine (stage1.4) in 30 ml of methanol and≈5 g of ammonia are heated at 120° C. for48 h in an autoclave. The reaction mixture is treated with silica gel,evaporated, applied to a silica gel column as a powder and finallyeluted with methylene chloride/methanol/THF (210:35:10). Filtration withmethanol through an alumina column (basic) and stirring in ethyl acetateyields 6-aminocarbonyl-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine;HPLC: t_(Ret)(Grad₂₀)=8.1; TLC-R_(f)=0.18 (CH₂Cl₂/methanol [10:1]); highresolution MS: (M+H)⁺=288.0669 (calc. 288.0652).

The starting material is obtained alternatively and advantageously asfollows:

Alternative stage 10.1: A mixture of 2.165 g (7.5 mmol) of6-carboxy-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine in 60 ml ofTHF and 10 ml of DMPU is heated under reflux for 30 min and then cooledto 0° C., whereupon a fine suspension is obtained. 824 μl (7.5 mmol) ofN-methylmorpholine followed by 981 μl (7.5 mmol of isobutylchloroformate in 10 ml of THF and, after 1 h at 0° C., 824 μl (7.5 mmol)of N-methylmorpholine followed by 981 μl (7.5 mmol) of isobutylchloroformate again are added dropwise. The mixture is stirred for 1 hand then added dropwise to 70 ml of a saturated solution of ammonia indioxane. After 3 h, the mixture is concentrated in vacuo. The residue ispoured into water, and the precipitate is filtered off and washed withwater and boiling isopropanol, whereupon6-aminocarbonyl-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine isobtained. Further product is obtained from the isopropanol filtrate.

EXAMPLE 11

57.5 mg (0.19 mmol) of4-(3-chloroanilino)-6-(thiocarbamoyl)-7H-pyrrolo[2,3-d]pyrimidine (seeExample 10) in 3 ml of methanol and 57.3 mg (0.25 mmol) of4-methoxyphenacyl bromide are heated to boiling for 17 h. Cooling of thepale yellow suspension, filtering and washing with isopropanol/diethylether yields4-(3-chloroanilino)-6-[4-(4-methoxyphenyl)thiazol-2-yl]-7H-pyrrolo[2,3-d]pyrimidine;HPLC: t_(Ret)(Grad₂₀)=15.4; TLC-R_(f)=0.33 (CH₂Cl₂/methanol=10:1);FAB-MS: (M+H)⁺=434.

EXAMPLE 12

57.5 mg (0.19 mmol) of4-(3-chloroanilino)-6-(thiocarbamoyl)-7H-pyrrolo[2,3-d]pyrimidine (seeExample 10) and 34 ml of 1-bromo-2-butanone (Aldrich; Milwaukee/USA) in3 ml of dioxane are heated to boiling for 2 h. Cooling, filtering thesuspension and washing with isopropanol/diethyl ether yields4-(3-chloroanilino)-6-(4-ethylthiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidine;HPLC: t_(Ret)(Grad₂₀)=13.6; FAB-MS: (M+H)⁺=356.

EXAMPLE 13

4-(3-Chloroanilino)-6-(4,5-dimethylthiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidineis obtained by the process described in this text.

EXAMPLE 14

19 mg (0.45 mmol) of lithium chloride and 19.5 mg (0.30 mmol) of sodiumazide are added to a solution of 80.9 mg (0.30 mmol) of4-(3-chloroanilino)-6-cyano-7H-pyrrolo[2,3-d]pyrimidine in 1 ml ofmethoxyethanol and the mixture is heated to boiling for 6.5 h. Thecooled reaction mixture is poured onto water/HCl (conc.) 10:1, themixture is stirred for 30 min, and the solid is filtered off and washedwith water. Dissolving the crystals in THF/isopropanol, partialevaporation to crystallization, filtering off and washing with diethylether affords4-(3-chloroanilino)-6-(tetrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine; HPLC:t_(Ret)(Grad₂₀)=9.5; TLC-R_(f)=0.45 (CH₂Cl₂/methanol=7:1); FAB-MS:(M+H)⁺=313.

The starting material is obtained as follows:

Stage 14.1: 13 ml of phosphorus oxychloride are added to 1.048 g (3.6mmol) of 6-aminocarbonyl-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine(see Stage 10.1) and 0.7 ml of N,N-dimethylacetamide. After stirring atRT for 1 h and at 100° C. for 4 h, the reaction mixture is poured intoan ice-cooled saturated solution of NaHCO₃. Extraction with ethylacetate (3 times), washing the organic layers with saturated NaHCO₃solution, water and saturated sodium chloride solution, drying (Na₂SO₄)and concentrating leads to a solid. Column chromatography (SiO₂; ethylacetate), and stirring the crude product in diethyl ether and hexaneyields 4-(3-chloroanilino)-6-cyano-7H-pyrrolo[2,3-d]pyrimidine; m.p.284-287° C.; TLC-R_(f)=0.71 (CH₂Cl2/methanol [10:1]);HPLC:t_(Ret)(Grad₂₀)=11.8.

EXAMPLE 15

50.4 mg (0.60 mmol) of NaHCO₃ and, at 0-5° C., 600 μl (0.60 mmol) ofmethyl iodide (1 M in dioxane) are added to 187.6 mg (0.60 mmol) of4-(3-chloroanilino)-6-(tetrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (seeExample 14) in 12 ml of DMF. After stirring at RT for 18 h, the mixtureis diluted with ethyl acetate, a little THF and water, and the aqueousphase is separated off and extracted again with ethyl acetate and alittle THF. The organic phases are washed twice with water and brine,dried with MgSO₄ and evaporated. Stirring the residue in THF/ethanolaffords a 2:1 mixture of4-(3-chloroanilino)-6-(2-methyltetrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidineand4-(3-chloroanilino)-6-(1-methyltetrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine;HPLC: t_(Ret)(Grad₂₀)=10.5 (1 part) and 10.7 (2 parts),¹H-NMR (DMSO-d₆)inter alia 4.45 (s, 2-H₃C-tetrazole), 4.32 (s, 1-H₃C-tetrazole); FAB-MS:(M+H)⁺=327.

EXAMPLE 16

0.1 g (0.304 mmol) of(R)-6-(4-aminophenyl)-4-[(1-phneylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidineand 0.026 ml (0.33 mmol) of methanesulfochloride in 1 ml of abs.dimethylacetamide are stirred at 0° C. for 4 h until starting materialis no longer present in the TLC. The reaction mixture is poured onto 10ml of ice water. It is extracted with ethyl acetate and 20 ml of anaqueous NaHCO₃ solution. The organic phase is washed with water, driedand concentrated,(R)-6-(4-methylsulfonylaminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidinecrystallizing out. The product is washed with hexane; m.p. 253-256° C.;FAB-MS: (M+H)⁺=408.

The starting material is obtained as follows:

Stage 16.1: Analogously to stage 19.4, boiling 6.0 g (220 mmol) of4-chloro-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (see Stage 19.3)with 6.04 g of (R)-(+)-1-phenylethylamine in 120 ml of n-butanol gives(R)-6-(4-nitrophenyl-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidineas rust-brown crystals of m.p.>250° C.

Stage 16.2: Analogously to stage 19.5, reduction of(R)-6-(4-nitrophenyl-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidinewith Raney nickel in THF/methanol gives(R)-6-(4-aminophenyl-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine;m.p. 234-235° C.; MS: M⁺=329.

EXAMPLE 17

Analogously to Example 16, the following are prepared from(R)-6-(4-aminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine(see stage 16.2) and the appropriate alkyl sulfochloride:

a)(R)-6-(4-ethylsulfonylaminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine;m.p. 260-261° C.; FAB-MS: (M+H)⁺=422, and

b)(R)-6-(4-isopropylsulfonylaminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]-pyrimidine;m.p. 262-263° C.; FAB-MS: (M+H)⁺=436.

EXAMPLE 18

Analogously to Example 16, the following are prepared from(R)-6-(3-aminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidineand the appropriate alkyl sulfochloride:

a)(R)-6-(3-methylsulfonylaminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine;m.p. 139-148° C. (amorphous); MS: (M⁺)=407,

b)(R)-6-(3-ethylsulfonylaminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine;m.p. 235-236° C.; FAB-MS: (M+H)⁺=422, and

c)(R)-6-(3-isopropylsulfonylaminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine;m.p. 257-258° C.; FAB-MS: (M+H)⁺=436.

The starting material is obtained as follows:

Stage 18.1: Analogously to the method described in stage 19.4, boiling20.0 g (700 mmol) of4-chloro-6-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (preparedanalogously to stages 19.1 to 19.3) with 23.1 ml (168 mmol) of(R)-phenylethylamine in 23.1 ml of n-butanol gives(R)-6-(3-nitrophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo-[2,3-d]pyrimidineas rust-brown crystals of m.p.>250° C.; MS: M⁺=359.

Stage 18.2: Analogously to stage 19.5, reduction of(R)-6-(3-nitrophenyl-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidinewith Raney nickel in THF/methanol gives(R)-6-(3-aminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine;m.p. 129-190° C. (amorphous); MS: M⁺=329.

EXAMPLE 19

Analogously to Example 16, the following are prepared from6-(4-aminophenyl)-4-(3-chloroanilino) -7H-pyrrolo[2,3-d]pyrimidine andthe corresponding alkyl sulfochloride:

a)6-(4-methylsulfonylaminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.; FAB-MS: (M+H)⁺=414,

b)4-(3-chloroanilino)-6-(4-ethylsulfonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.; FAB-MS: (M+H)⁺=428,

c)4-(3-chloroanilino)-6-(4-isopropylsulfonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.; FAB-MS: (M+H)⁺=442 and

d)4-(3-chloroanilino)-6-(4-phenylsulfonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.; FAB-MS: (M+H)⁺=475.

The starting material is obtained as follows:

Stage 19.1: In a dry three-necked flask, 75 ml of abs. ethanol and 6.5 g(390 mmol) of ethyl 2-amidinoacetate hydrochloride [for preparation see:Liebigs Ann. Chem., 1895 (1977)] are initially introduced under argon,and the mixture is cooled to 0-5° C. and treated with 2.65 g (390 mmol)of sodium ethoxide. 5 g (195 mmol) of2-bromo-1-(4-nitrophenyl)ethan-1-one are then added, and the mixture isallowed to come to RT and is stirred further for 48 h. The reactionmixture is then partitioned between water and ethyl acetate. The ethylacetate phase is washed three times with water and once with satd NaClsolution, dried and filtered, and the filtrate is evaporated. Thered-brown residue is suspended in hexane,2-amino-3-ethoxycarbonyl-5-(4-nitrophenyl)pyrrole precipitating as acrude product (purity 93%) which is used for the next stage withoutfurther purification; MS: (M)⁺=275.

Stage 19.2: 2.5 g (97 mmol) of2-amino-3-ethoxycarbonyl-5-(4-nitrophenyl)pyrrole, 19.4 ml of formamide,9.7 ml of DMF and 3.1 ml of formic acid are stirred at 150° C. togetherfor 22 h. 1 ml of isopropanol is added to the warm reaction mixture.After cooling the reaction mixture, the precipitated product is filteredoff. It is washed successively three times with 10 ml of ethanol eachtime, twice with 10 ml of isopropanol each time and twice with 10 ml ofhexane each time.4-Hydroxy-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine is obtained asrust-brown crystals which are employed for the next stage; MS: (M)⁺=256.

Stage 19.3: By heating4-hydroxy-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine with POCl₃,4-chloro-6-(4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine is prepared(purity 93%); m.p.>280° C.; FAB-MS: (M+H)⁺=275.

Stage 19.4: By boiling 0.25 g (0.91 mmol) of4-chloro-6-(4-nitrophenyl)-7H-pyrrolo-[2,3-d]pyrimidine with 0.19 ml of3-chloroaniline in 5 ml of n-butanol,4-(3-chloroanilino)-6-4-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine isobtained as rust-brown crystals; m.p.>250° C.; ¹H-NMR (360 Mhz,DMSO-d₆): 12.95 (s, pyrrole-NH), 10.3 (s, aniline-NH), 8.45 (s,pyrimidine-H), 8.24 (s, aromatic H), 7.18-8.4 (7 aromatic H+pyrrole-5H);MS: (M)⁺=365.

Stage 19.5: 150 mg (0.41 mmol) of4-(3-chloroanilino)-6-(4-nitrophenyl)-7H-pyrrolo-[2,3-d]pyrimidine arehydrogenated with 50 mg of Raney nickel in 20 ml of THF/methanol at RTand normal pressure for 5 h, the desired product precipitating in thecourse of this. The catalyst is filtered off and the filter residue iswashed with warm THF. The filtrate is evaporated to dryness. The crudeproduct is purified by digesting several times in methanol andprecipitating from THF/hexane, whereupon6-(4-aminophenyl)-4-(3-chloroanilino)7H-pyrrolo[2,3-d]pyrimidine isobtained as pale beige crystals; m.p.>290° C.; ¹H-NMR (360 MHz,DMSO-d₆): 12.05 (s, pyrrole-NH), 9.38 (s, aniline-NH), 8.31 (s,pyrimidine-H), 8.24 (s, aromatic H), 7.80 (d, aromatic H), 7.53 (d, 2aromatic H), 7.35 (t, aromatic H), 7.05 (d, aromatic H), 6.90 (s,pyrrole-5H), 6.64 (d, 2 aromatic H), 5.35 (s, NH2); MS: (M)⁺=335.

EXAMPLE 20

Analogously to Example 16, the following are prepared from6-(3-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine andthe corresponding alkyl sulfochloride:

a)4-(3-chloroanilino)-6-(3-methylsulfonylaminophenyi)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.; FAB-MS: (M+H)⁺=414,

b)4-(3-chloroanilino)-6-(3-ethylsulfonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p. 228-230° C.; FAB-MS: (M+H)⁺=428, and

c)4-(3-chloroanilino)-6-(3-isopropylsulfonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p. 233° C.; FAB-MS: (M+H)⁺=442.

The starting material is obtained as follows:

Stage 20.1: Analogously to stage 19.4, boiling 2.0 g (7.28 mmol) of4-chloro-6-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine with 4.2 ml (40mmol) of 3-chloroaniline in 150 ml of n-butanol gives6-(3-nitrophenyl-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine asyellowish crystals of m.p.>250° C.; MS: M⁺=365.

Stage 20.2: Analogously to stage 19.5, reduction of6-(3-nitrophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine withRaney nickel in THF/methanol gives6-(3-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine; m.p.293-295° C.; MS: M⁺−336.

EXAMPLE 21

0.2 g (0.56 mmol) of6-(4-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine (seestage 19.5), 0.097 ml (0.67 mmol) of N,N-dimethylformamide dimethylacetal and 0.112 ml (0.73 mmol) of triethylamine are stirred at RT for24 h in 10 ml of THF until all the starting material has disappeared inthe TLC. The reaction solution is concentrated to dryness in vacuo andthe residue is chromatographed on a silica gel column. Crystallizationfrom THF/hexane or ethyl acetate/hexane gives4-(3-chloroanilino)-6-(4-[dimethylamino-methylenamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.; MS: (M)⁺=390.

EXAMPLE 22

Analogously to Example 21, the following compounds are prepared from6-(4-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine (seestage 19.5) and the corresponding N,N-dialkylformamide dimethyl acetalor heterocyclyl aldehyde dimethyl acetal:

a)4-(3-chloroanilino)-6-(4-diethylaminomethylenamino]phenyl)-[7H-pyrrolo[2,3-d]pyrimidine;m.p.>310° C.; FAB-MS: (M+H)⁺=419,

b)4-(3-chloroanilino)-6-(4-[piperidinomethylenaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.; MS: (M)⁺=430,

c)4-(3-chloroanilino)-6-(4-[morpholinomethylenamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>310° C.; MS: (M)⁺=432, and

d)4-(3-chloroanilino)-6-{4-[(4-methylpiperazino)methylenamino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine;m.p.>310° C.; FAB-MS: (M+H)⁺=446.

EXAMPLE 23

Analogously to Example 21, the following compounds are prepared from6-(3-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine (seestage 20.2) and the corresponding N,N-dialkylformamide dimethyl acetalor morpholinoaldehyde dimethyl acetal:

a)4-(3-chloroanilino)-6-(3-[dimethylaminomethylenamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p. 266-268° C.; MS: (M)⁺=390,

b)4-(3-chloroanilino)-6-(3-[diethylaminomethylenamino]-phenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p. 171-172° C.; FAB-MS: (M+H)⁺=419, and

c)4-(3-chloroanilino)-6-(3-[morpholinomethylenamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p. 284-286° C.; FAB-MS: (M+H)⁺=433.

EXAMPLE 24

Analogously to Example 21, the following compound is prepared from(R)-6-(4-aminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine(see stage 16.2) and N,N-dimethylformamide dimethyl acetal:

(R)-6-(4-[dimethylaminomethylenamino]phenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.; MS: (M+H)⁺=385.

EXAMPLE 25

Analogously to Example 21, the following compound is prepared from(R)-6-(3-aminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine(see stage 18.2) and N,N-dimethylformamide dimethyl acetal:

(R)-6-(3-[dimethylaminomethylenamino]phenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine;m.p. 267-269° C.; FAB-MS: (M+H)⁺=385.

EXAMPLE 26

738 mg (2.02 mmol) of6-(4-carbonylphenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine arestirred at room temperature for 3 h with 3 equivalents of morpholine and3.5 equivalents of DEPC (Aldrich) in DMF. The reaction solution ispoured onto water and the solid is filtered off and washed with waterand methanol. The product obtained is chromatographed on silica gel andeluted with chloroform/methanol/acetic acid/water (850:130:15:5; v/v).The product obtained is digested in diethyl ether, filtered off anddried.4-(3-Chloroanilino-6-(4-[morpholin-4-yl-carbonyl]phenyl)-7H-pyrrolo[2,3-d]pyrimidineis obtained as beige crystals; m.p.>250° C.; FAB-MS: (M+H)⁺=434.

EXAMPLE 27

Analogously to Example 26, starting from(3-chloroanilino)-6-(4-carbonylphenyl)-7H-pyrrolo[2,3-d]pyrimidine andN-methylpiperazine4-(3-chloroanilino)6-(4-[4-methylpiperazin-1-yl]-carbonylphenyl)-7H-pyrrolo[2,3-d]pyrimidineis obtained; m.p. 250° C.; FAB-MS: (M+H)⁺=447.

EXAMPLE 28

300 mg (0.89 mmol) of6-(4-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine (seeStage 19.5), dissolved in 20 ml of abs. THF and 2 ml (3.56 mmol) of DMAare treated with 0.29 ml of ethyl isocyanate (FLUKA) with exclusion ofmoisture and heated under reflux until starting material is no longerpresent in the TLC (24 h). The reaction mixture is evaporated to drynessin vacuo and the crude product is chromatographed on silica gel, ethylacetate/methanol being used as the eluent. Fractions which contain thedesired product are combined and evaporated to dryness. The residue isdissolved in a little THF. The target compound isprecipitated/crystallized by addition of n-hexane. Colorless crystals of4-(3-chloroanilino)-6-(4-[N³-ethylureido]phenyl)-7H-pyrrolo[2,3-d]pyrimidineare obtained; m.p.>290° C., FAB-MS: (M+H)⁺=407.

EXAMPLE 29

Analogously to Example 28, the following compounds are prepared from6-(3-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine (seeStage 20.2) and the corresponding alkyl isocyanate or phenyl isocyanate:

a)4-(3-chloroanilino)-6-(3-[N³-ethylureidophenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.; FAB-MS: (M+H)⁺=407, and

b)4-(3-chloroanilino)-6-(3-[N³-phenylureidophenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.; FAB-MS: (M+H)⁺=455.

EXAMPLE 30

Analogously to Example 28,(R)-6-(4-[N³-ethylureido]phenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidineis prepared from(R)-6-(4-aminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine(see Stage 16 . . . ) and ethyl isocyanate; m.p. 238-240° C.; FAB-MS:(M+H)⁺=401.

EXAMPLE 31

Analogously to Example 28,(R)-6-(3-[N³-ethylureido]-phenyl)-4-[(1-phenylethyl)amino]7H-pyrrolo[2,3-d]pyrimidineis prepared from(R)-6-(3-aminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine(see Stage 18.2) and ethyl isocyanate; m.p. 177-178° C.; FAB-MS:(M+H)⁺=401.

EXAMPLE 32

Analogously to the method described in Example 28, 300 mg (0.89 mmol) of6-(4-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine (seeStage 19.5) dissolved in 20 ml of abs. THF and 2 ml of DMA, and 0.27 ml(3.56 mmol) of methyl isothiocyanate (EGA) yield, afterrecrystallization from THF-n-hexane,4-(3-chloroanilino)-6-(4-[N³-ethylthioureido]phenyl)-7H-pyrrolo[2,3-d]pyrimidinein the form of colorless crystals; m.p. 275-276° C.; FAB-MS: (M+H)⁺=409.

EXAMPLE 33

Analogously to Example 32,6-(3-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine andmethyl isothiocyanate yield4-(3-chloroanilino)-6-(3-(N³-methylthioureido]phenyl)-7H-pyrrolo[2,3-d]pyrimidine:m.p. 198-200° C.; FAB-MS: (M+H)⁺=409.

EXAMPLE 34

Analogously to Example 32,(R)-6-(4-aminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine(see Stage 16.2) and methyl isothiocyanate yield(R)-6-(4-[N³-methylthioureido]phenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]-pyrimidine;m.p. 225-228° C.; FAB-MS: (M+H)⁺=403.

EXAMPLE 35

Analogously to Example 32,(R)-6-(3-aminophenyl)-4-[(1-phenylethyl)amino-]7H-pyrrolo[2,3-d]-pyrimidine(see Stage 18.2) and methyl isothiocyanate yield(R)-6-(3-[N³-methylthioureido]phenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine;m.p. 188-190° C.; FAB-MS: (M+H)⁺=403.

EXAMPLE 36

300 mg (0.89 mmol) of6-(4-aminophenyl-4-(3-chloroanilino)-7H-pyrrolo-[2,3-d]pyrimidine (seeStage 19.5), dissolved in 2.7 ml of abs. dioxane and 0.13 ml of2,6-lutidine, are treated with a solution of 0.10 ml (0.98 mmol) ofmethyl chloroformate in 1.8 ml of abs. dioxane with the exclusion ofmoisture and stirred at RT until starting material is no longer presentin the TLC. The reaction mixture is added to 50 ml of water. It is thenextracted with 200 ml of ethyl acetate and 10 ml of 5% aqueous sodiumhydrogencarbonate solution. The combined ethyl acetate phases are washed3 times with water, dried and evaporated in vacuo. The residue ischromatographed on silica gel, eluting with methylene chloride andincreasing amounts of methanol. The target compound,⁴-(3-chloroanilino)-6-(4-methoxycarbonylaminophenyl)-7H-pyrrolo-[2,3-d]pyrimidine,is crystallized from methanol or acetone in the form of slightlyyellow-colored crystals; m.p.>300° C.; FAB-MS: (M+H)⁺=394.

EXAMPLE 37

Analogously to Example 36, the following compounds are prepared from6-(4-aminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine (seeStage 19.5) and the corresponding alkyl chloroformate:

a)4-(3-chloranilino)-6-(4-ethoxycarbonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.; FAB-MS: (M+H)⁺=408,

b)4-(3-chloroanilino)-6-(4-isopropyloxycarbonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.; FAB-MS: (M+H)⁺=422 and

c)4-(3-chloroanilino)-6-{4-[(2-methylpropyloxy)carbonylamino]phenyl}-7H-pyrrolo-[2,3-d]pyrimidine;m.p.>282-284° C.; FAB-MS: (M+H)⁺=436.

EXAMPLE 38

3.53 g (9.0 mmol) of4-(3-chloroanilino)-6-(4-ethoxycarbonylphenyl)-7H-pyrrolo[2,3-d]pyrimidineare suspended in 150 ml of THF. At 54° C., a total of 0.845 g (21.6mmol) of lithium aluminum hydride are introduced in the course of 5 h.For working up, 1 ml of water, 2 ml of 1N sodium hydroxide solution and1 ml of water, followed by 10 g of sodium sulfate, are addedsuccessively. The solid is filtered off and the filtrate isconcentrated. The residue obtained is washed with methanol and diethylether and then dried.4-(3-Chloroanilino)-6-(4-hydroxymethlyphenyl)-7H-pyrrolo[2,3-d]pyrimidineis obtained in colorless crystals; m.p.>250° C.; FAB-MS (M+H)⁺=351.

EXAMPLE 39

The following compounds are obtained analogously to the processesdescribed in this text:

a)(R)-6-(3-benzylaminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine;m.p. 253-255° C.,

b)6-(4-benzyloxy-3-methoxyphenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine;m.p. 237-238° C.,

c)6-(4-benxyloxy-3-methoxyphenyl)-4-(3-methylanilino)-7H-pyrrolo[2,3-d]pyrimidine;m.p. 231-234° C.,

d)6-(4-hydroxy-3-methoxyphenyl)-4-(3-methylanilino)-7H-pyrrolo[2,3-d]pyrimidine;m.p. 234-236° C.,

e) 4-anilino-6-(4-hydroxy-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidinehydrochloride; m.p. 242-246° C.,

f) 4-(3-chloroanilino)-6-(4-hydroxy-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride; m.p.>250° C.,

g)4-(3-chloroanilino)-6-(4-(fur-2-yl-carbonylamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.,

h)4-(3-chloroanilino)-6-(4-(thien-2-yl-carbonylamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p>300° C.;

i)6-(4-benzylaminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine;m.p.>300° C.,

j)(R)-6-(4-methoxyphenyl-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine;m.p. 256-257° C.,

k)4-(3-chloroanilino)-6-{4-[(1-dimethylamino-1-isopropylmethylen)amino}phenyl)-7H-pyrrolo[2,3-d]pyrimidine;m.p. 255-257° C., and

l) 4-(3-chloroanilino)-6-(thiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidine.

EXAMPLE 40

Dry-filled Capsules

5000 capsules, each comprising as active ingredient 0.25 g of one of thecompounds of the formula I mentioned in the preceding Examples, areprepared as follows:

Composition

active ingredient 1250 g talc 180 g wheat starch 120 g magnesiumstearate 80 g lactose 20 g

Preparation process: The substances mentioned are pulverized and forcedthrough a sieve of 0.6 mm mesh size. 0.33 g portions of the mixture aredispensed into gelatin capsules using a capsule-filling machine.

EXAMPLE 41

Soft Capsules

5000 soft gelatin capsules, each comprising as active ingredient 0.05 gof one of the compounds of the formula I mentioned in the precedingExamples, are prepared as follows:

active ingredient 250 g Lauroglycol 2 liters

Preparation process: The pulverized active ingredient is suspended inLauroglycol® (propylene glycol laurate, Gattefoss{acute over (e)} S. A.,Saint Priest, France) and ground in a wet pulverizer to a particle sizeof approx. 1 to 3 μm. 0.419 g portions of the mixture are then dispensedinto soft gelatin capsules using a capsule-filling machine.

EXAMPLE 42

Soft Capsules

5000 soft gelatin capsules, each comprising as active ingredient 0.05 gof one of the compounds of the formula I mentioned in the precedingExamples, are prepared as follows:

Composition

active ingredient 250 g PEG 400 1 liter Tween 80 1 liter

Preparation process: The pulverized active ingredient is suspended inPEG 400 (polyethylene glycol having an M_(r) of from approx. 380 toapprox. 420, Fluka, Switzerland) and Tween®80 (polyoxyethylene sorbitanmonolaurate, Atlas Chem. Ind. Inc., USA, supplied by Fluka, Switzerland)and ground in a wet pulverizer to a particle size of approx. 1 to 3 μm.0.43 g portions of the mixture are then dispensed into soft gelatincapsules using a capsule-filling machine.

What is claimed is:
 1. A compound of formula I

in which n is 0 to 3, q is 0 or 1, R is halogen, lower alkyl,hydroxymethyl, aminomethyl, hydroxyl, lower alkanoyloxy, lower alkoxy,carboxyl, lower alkanoyl, benzoyl, lower alkoxycarbonyl, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, cyano, amino, loweralkanoylamino, lower alkylamino, N,N-di-lower alkylamino ortrifluoromethyl, it being possible, if two or more radicals R arepresent in the molecule, for these to be identical to or different fromone another, one of the radicals R₁ and R₂ is hydrogen or lower alkyl,and the other of the radicals R₁ and R₂ is a) a radical of the formulaII

 in which u is 1 to 3 and one or more radicals R₄ is selected from thegroup consisting of amidino, guanidino, ureido, N³-lower alkylureido,N³,N³-di-lower alkylureido, N³-phenylureido, N³,N³-diphenylureido,thiocarbamoyl, thioureido, N³-lower alkylthioureido, N³,N³-di-loweralkylthioureido, lower alkoxycarbonylamino, benzyloxycarbonylamino,morpholine-4-carbonyl, piperazine-1-carbonyl, 4-loweralkylpiperazine-1-carbonyl, lower alkylsulfonylamino,benzenesulfonylamino, toluenesulfonylamino, thiophene-2-carbonylamino,furan-2-carbonylamino, benzylamino, hydroxymethyl, aminomethyl or aradical of the formula —N═C(R₅)—R₆, in which R₅ is hydrogen or loweralkyl and R₆ is di-lower alkylamino, piperidino, 4-lower alkylpiperazinoor morpholino, and the other radical(s) R₄ is (are) halogen, loweralkyl, hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, loweralkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylcarbamoyl, cyano, amino, lower alkanoylamino, lower alkylamino,N,N-di-lower alkylamino or trifluoromethyl, it being possible, if two ormore radicals R₄ are present in the molecule, for these to be identicalto or different from one another, or is b) a radical of the formula III

 in which R₇ is lower alkoxy or benzyloxy and R₈ is hydroxyl orbenzyloxy, or is c) amino-lower alkyl, in which the amino group issubstituted by one or two hydroxy-lower alkyl, amino-lower alkyl,carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl,benzyloxycarbonyl-lower alkyl or benzyl radicals, which in the phenylmoiety are unsubstituted or substituted by halogen, lower alkyl,hydroxymethyl, aminomethyl, hydroxyl, lower alkanoyloxy, lower alkoxy,carboxyl, lower alkanoyl, benzoyl, lower alkoxycarbonyl, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, cyano, amino, loweralkanoylamino, lower alkylamino, N,N-di-lower alkylamino ortrifluoromethyl, or is d) piperidine-1-carbonyl, piperazine-1-carbonyl,4-lower alkylpiperazine-1-carbonyl, morpholine-4-carbonyl,thiocarbamoyl, a heterocyclic radical bonded via a ring carbon atom andhaving five ring members and 1-4 ring heteroatoms, selected from oxygen,nitrogen and sulfur, or is e) 4-lower alkylpiperazinomethyl or a loweralkyl radical which is substituted by a heterocyclic radical other thanpiperazinyl and having five or six ring members and 1-4 ringheteroatoms, selected from oxygen, nitrogen and sulfur, or is f) aradical of the formula —CH═N—OR₉ in which R₉ is hydrogen or lower alkyl,or g) if q is 1, additionally to the definitions given above in thesections a) to f) can also be phenyl which is substituted by halogen,lower alkyl, trifluoromethyl or lower alkoxy, and R₃ is hydrogen, loweralkyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl orN,N-di-lower alkylcarbamoyl, or a salts thereof.
 2. A compound of theformula I according to claim 1 in which R₁ is hydrogen, R₂ is pyrrolyl,thienyl, furyl, tetrazol-5-yl which is unsubstituted or substituted bylower alkyl or thiazol-2-yl which is unsubstituted or substituted bylower alkoxyphenyl, or methyl which is substituted by pyrrolyl, thienyl,furyl, morpholino, 4-lower alkylpiperazin-1-yl, tetrazol-5-yl which isunsubstituted or substituted by lower alkyl, or thiazol-2-yl which isunsubstituted or substituted by lower alkoxyphenyl, and the otherradicals and symbols are as defined in claim 1, or a salt thereof.
 3. Acompound of the formula I according to claim 1 in which n is 0 or 1, qis 0 or 1, R is chlorine, R₁ is hydrogen, R₂ is a) a radical of theformula II

 in which u is 1 and R₄ is N³-lower alkylureido, N³-phenylureido,N³-lower alkylthioureido, lower alkoxycarbonylamino,benzyloxycarbonylamino, morpholine-4-carbonyl, piperazine-1-carbonyl,4-lower alkylpiperazine-1-carbonyl, lower alkylsulfonylamino,benzenesulfonylamino, toluenesulfonylamino, furan-2-carbonylamino,thiophene-2-carbonylamino, benzylamino, hydroxymethyl or a radical ofthe formula —N═C(R₅)—R₆ in which R₅ is hydrogen or lower alkyl and R₆ isdi-lower alkylamino, piperidino, 4-lower alkylpiperazino or morpholino,or is b) a radical of the formula III

 in which R₇ is lower alkoxy and R₈ is hydroxyl or benzyloxy, or is c)aminomethyl in which the amino group is substituted by one or twohydroxy-lower alkyl or benzyl radicals which in the phenyl moiety areunsubstituted or substituted by hydroxyl or lower alkoxy, or is d)piperazine-1-carbonyl, 4-lower alkylpiperazine-1-carbonyl,morpholine-4-carbonyl, thiocarbamoyl, thiazol-2-yl,4-(4-methoxyphenyl)thiazol-2-yl, 4-ethylthiazol-2-yl,4,5-dimethylthiazol-2-yl, tetrazol-5-yl, 2-methyltetrazol-5-yl or1-methyltetrazol-5-yl, or is e) 4-lower alkylpiperazinomethyl ormorpholinomethyl, or is f) a radical of the formula —CH═N—OR₉, in whichR₉ is hydrogen or lower alkyl, or g) if q is 1, additionally to thedefinitions given above in sections a) to f) can also be phenyl which issubstituted by lower alkoxy, and R₃ is hydrogen or lower alkyl, or apharmaceutically acceptable salt thereof.
 4. A compound of the formula Iaccording to claim 1, selected from4-(3-chloroanilino)-6-[(4-methylpiperazin-1-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(morpholin-4-yl)methyl]-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-[bis(2-hydroxyethyl)aminomethyl)]-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-[(4-methoxybenzylamino)methyl]-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-[(4-hydroxybenzylamino)methyl]-7H-pyrrolo[2,3-d]pyrimidine,(E)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehydeoxime,(Z)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehydeoxime, 4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehydeO-methyoxime,4-(3-chloroanilino)-6-(morpholin-4-yl-carbonyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-[(4-methylpiperazin-1-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(thiocarbamoyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-[4-(4-methoxyphenyl)thiazol-2-yl]-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-ethylthiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4,5-dimethylthiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(tetrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(2-methyltetrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(1-methyltetrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(4-methylsulfonylaminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(4-ethylsulfonylaminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(4-isopropylsulfonylaminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(3-methylsulfonylaminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(3-ethylsulfonylaminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(3-isopropylsulfonylaminophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine,6-(4-methylsulfonylaminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-ethylsulfonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-isopropylsulfonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-phenylsulfonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(3-methylsulfonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(3-ethylsulfonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(3-isopropylsulfonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-[dimethylaminomethylenamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-[diethylaminomethylenamino]phenyl-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-[piperidinomethylenaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-[morpholinomethylenamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-{4-[(4-methylpiperazino)methylenamino]phenyl}-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(3-[dimethylaminomethylenamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(3-[diethylaminomethylenamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(3-[morpholinomethylenamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(4-[dimethylaminomethylenamino]phenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(3-[dimethylaminomethylenamino]phenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-[morpholin-4-ylcarbonyl]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-[4-methylpiperazin-1-ylcarbonyl]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-[N³-ethylureido]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(3-[N³-ethylureido]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(3-[N³-phenylureidophenyl)-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(4-[N³-ethylureido]phenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(3-[N³-ethylureido]phenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-[N³-methylthioureido]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(3-[N³-methylthioureido]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(4-[N³-methylthioureido]phenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(3-[N³-methylthioureido]phenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-methoxycarbonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-ethoxycarbonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-isopropyloxycarbonylaminophenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-[(2-methylpropyloxy)carbonylamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(3-benzylaminophenyl)-4-[(l-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine, 6-(4-benzyl oxy-3-methoxyphenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine,6-(4-benzyloxy-3-methoxyphenyl)-4-(3-methylanilino)-7H-pyrrolo[2,3-d]pyrimidine,6-(4-hydroxy-3-methoxyphenyl)-4-(3-methylanilino)-7H-pyrrolo[2,3-d]pyrimidine,4-anilino-6-(4-hydroxy-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidinehydrochloride,4-(3-chloroanilino)-6-(4-hydroxy-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-hydrochloride,4-(3-chloroanilino)-6-(4-[fur-2-ylcarbonylamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-[thien-2-ylcarbonylamino]phenyl)-7H-pyrrolo[2,3-d]pyrimidine,6-(4-benzylaminophenyl)-4-(3-chloroanilino)-7H-pyrrolo[2,3-d]pyrimidine,(R)-6-(4-methoxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine,4-(3-chloroanilino)-6-(4-[(1-dimethylamino-1-isopropylmethylene)amino}phenyl)-7H-pyrrolo[2,3-d]pyrimidineand 4-(3-chloroanilino)-6-(thiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidine, ora pharmaceutically acceptable salt thereof.
 5. A process for thepreparation of a 7H-pyrrolo[2,3-d]pyrimidine derivative of the formula I

in which n is 0 to 3, q is 0 or 1, R is halogen, lower alkyl,hydroxymethyl, aminomethyl, hydroxyl, lower alkanoyloxy, lower alkoxy,carboxyl, lower alkanoyl, benzoyl, lower alkoxycarbonyl, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, cyano, amino, loweralkanoylamino, lower alkylamino, N,N-di-lower alkylamino ortrifluoromethyl, it being possible, if two or more radicals R arepresent in the molecule, for these to be identical to or different fromone another, one of the radicals R₁ and R₂ is hydrogen or lower alkyl,and the other of the radicals R₁ and R₂ is a) a radical of the formulaII

 in which u is 1 to 3 and at least one radical R₄ is amidino, guanidino,ureido, N³-lower alkylureido, N³,N³-di-lower alkylureido,N³-phenylureido, N³,N³-diphenylureido, thiocarbamoyl, thioureido,N³-lower alkylthioureido, N³,N³-di-lower alkylthioureido, loweralkoxycarbonylamino, benzyloxycarbonylamino, morpholine-4-carbonyl,piperazine-1-carbonyl, 4-lower alkylpiperazine-1-carbonyl, loweralkylsulfonylamino, benzenesulfonylamino, toluenesulfonylamino,thiophene-2-carbonylamino, furan-2-carbonylamino, benzylamino,hydroxymethyl, aminomethyl or a radical of the formula —N═C(R₅)—R₆, inwhich R₅ is hydrogen or lower alkyl and R₆ is di-lower alkylamino,piperidino, 4-lower alkylpiperazino or morpholino, and the otherradical(s) R₄ is (are) halogen, lower alkyl, hydroxyl, loweralkanoyloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, cyano, amino, loweralkanoylamino, lower alkylamino, N,N-di-lower alkylamino ortrifluoromethyl, it being possible, if two or more radicals R₄ arepresent in the molecule, for these to be identical to or different fromone another, or is b) a radical of the formula III

 in which R₇ is lower alkoxy or benzyloxy and R₈ is hydroxyl orbenzyloxy, or is c) amino-lower alkyl, in which the amino group issubstituted by one or two hydroxy-lower alkyl, amino-lower alkyl,carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl,benzyloxycarbonyl-lower alkyl or benzyl radicals, which in the phenylmoiety are unsubstituted or substituted by halogen, lower alkyl,hydroxymethyl, aminomethyl, hydroxyl, lower alkanoyloxy, lower alkoxy,carboxyl, lower alkanoyl, benzoyl, lower alkoxycarbonyl, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, cyano, amino, loweralkanoylamino, lower alkylamino, N,N-di-lower alkylamino ortrifluoromethyl, or is d) piperidine-1-carbonyl, piperazine-1-carbonyl,4-lower alkylpiperazine-1-carbonyl, morpholine-4-carbonyl,thiocarbamoyl, a heterocyclic radical bonded via a ring carbon atom andhaving five ring members and 1-4 ring heteroatoms, selected from oxygen,nitrogen and sulfur, or is e) 4-lower alkylpiperazinomethyl or a loweralkyl radical which is substituted by a heterocyclic radical other thanpiperazinyl and having five or six ring members and 1-4 ringheteroatoms, selected from oxygen, nitrogen and sulfur, or is f) aradical of the formula —CH═N—OR₉ in which R₉ is hydrogen or lower alkyl,or g) if q is 1, additionally to the definitions given above in thesections a) to f) can also be phenyl which is substituted by halogen,lower alkyl, trifluoromethyl or lower alkoxy, and R₃ is hydrogen, loweralkyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl orN,N-di-lower alkylcarbamoyl, or a salt thereof, which comprises a)reacting a pyrrolo[2,3-d]pyrimidine derivative of the formula IV

 in which X is a suitable leaving group, Z is hydrogen or 1-aryl-loweralkyl and the other substituents are as defined above for compounds ofthe formula I, free functional groups present in the radicals R₁ and R₂if necessary being protected by easily removable protective groups, withan aniline derivative of the formula V

 in which R, R₃, n and q are as defined above for compounds of theformula I, free functional groups present in the radical R if necessarybeing protected by easily removable protective groups, and removingprotective groups present and, if present, the 1-aryl-lower alkylradical Z, or b) reacting a pyrrolo[2,3-d]pyrimidin-4-one derivative ofthe formula VI

 in which Z′ is 1-aryl-lower alkyl and R₁ and R₂ are as defined abovefor compounds of the formula I, free functional groups present in theradicals R₁ and R₂ if necessary being protected by easily removableprotective groups, in the presence of a dehydrating agent and a tertiaryamine, with a phenylamine of the formula V above and removing protectivegroups present, or c) for the preparation of a compound of the formula Iin which the radical R is hydroxyl or in which one of the radicals R₁ orR₂ is amino-lower alkyl in which the amino group is substituted by oneor two benzyloxycarbonyl-lower alkyl or benzyl radicals which aresubstituted by hydroxyl in the phenyl moiety, and the other substituentsare as defined above for compounds of the formula I, reacting a compoundof the formula I in which the radical R is methoxy or in which one ofthe radicals R₁ or R₂ is amino-lower alkyl in which the amino group issubstituted by one or two benzyloxycarbonyl-lower alkyl or benzylradicals which are substituted by methoxy in the phenyl moiety, and theother substituents are as defined above for compounds of the formula I,free functional groups present in the radicals R, R₁ and R₂ if necessarybeing protected by easily removable protective groups, with borontribromide, and removing protective groups present, or d) for thepreparation of a compound of the formula I in which one of the radicalsR₁ and R₂ is aminomethyl in which the amino group is substituted by oneor two hydroxy-lower alkyl, amino-lower alkyl, carboxy-lower alkyl,lower alkoxycarbonyl-lower alkyl, benzyloxycarbonyl-lower alkyl orbenzyl radicals which in the phenyl moiety are unsubstituted orsubstituted by halogen, lower alkyl, hydroxymethyl, aminomethyl,hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkanoyl,benzoyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylcarbamoyl, cyano, amino, lower alkanoylamino, loweralkylamino, N,N-di-lower alkylamino or trifluoromethyl, or in which oneof the radicals R₁ and R₂ is 4-lower alkylpiperazinomethyl,morpholinomethyl or piperidinomethyl, and the other substituents are asdefined above for compounds of the formula I, reacting a compound of theformula I in which one of the radicals R₁ and R₂ is formyl and the othersubstituents are as defined above for compounds of the formula I, freefunctional groups present in the radical R if necessary being protectedby easily removable protective groups, with an amine of the formula VIIHN(R₁₀)R₁₁  (VII)  in which α) R₁₀ is hydrogen, hydroxy-lower alkyl,amino-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-loweralkyl, benzyloxycarbonyl-lower alkyl or benzyl, thebenzyloxycarbonyl-lower alkyl or benzyl radicals in the phenyl moietybeing unsubstituted or substituted by halogen, lower alkyl,hydroxymethyl, aminomethyl, hydroxyl, lower alkanoyloxy, lower alkoxy,carboxyl, lower alkanoyl, benzoyl, lower alkoxycarbonyl, carbamoyl,N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, cyano, amino, loweralkanoylamino, lower alkylamino, N,N-di-lower alkylamino ortrifluoromethyl, and R₁₁ is hydroxy-lower alkyl, amino-lower alkyl,carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl,benzyloxycarbonyl-lower alkyl or benzyl, the benzyloxycarbonyl-loweralkyl or benzyl radicals in the phenyl moiety being unsubstituted orsubstituted by halogen, lower alkyl, hydroxymethyl, aminomethyl,hydroxyl, lower alkanoyloxy, lower alkoxy, carboxyl, lower alkanoyl,benzoyl, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylcarbamoyl, cyano, amino, lower alkanoylamino, loweralkylamino, N,N-di-lower alkylamino or trifluoromethyl, or β) in whichthe radicals R₁₀ and R₁₁ together are pentane-1,5-diyl, 3-N-loweralkyl-3-azapentane-1,5-diyl or 3-oxapentane-1,5-diyl, catalyticallyhydrogenating the product and then removing protective groups present,or e) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is a radical of the formula —CH═N—OR₉ in which R₉is hydrogen or lower alkyl, and the other substitutents are as definedabove for compounds of the formula I, reacting a compound of the formulaI, in which one of the radicals R₁ and R₂ is formyl and the othersubstituents are as defined above for compounds of the formula I, freefunctional groups present in the radical R if necessary being protectedby easily removable protective groups, with a hydroxylamine derivativeof the formula VIII H₂N—O—R₁₂  (VIII)  in which R₁₂ is hydrogen or loweralkyl, and removing protective groups present, or f) for the preparationof a compound of the formula I in which one of the radicals R₁ and R₂ ispiperidine-1-carbonyl, piperazine-1-carbonyl, 4-loweralkylpiperazine-1-carbonyl or morpholine-4-carbonyl, and the othersubstituents are as defined above for compounds of the formula I,reacting a compound of the formula I in which one of the radicals R₁ andR₂ is carboxyl and the other substituents are as defined above forcompounds of the formula I, free functional groups present in theradical R if necessary being protected by easily removable protectivegroups, or a reactive carboxylic acid derivative of such a compound,with an amine of the formula VII HN(R₁₀)R₁₁  (VII)  in which theradicals R₁₀ and R₁₁ together are pentane-1,5-diyl,3-azapentane-1,3-diyl, 3-N-lower alkyl-3-azapentane-1,3-diyl or3-oxapentane-1,3-diyl, and then removing protective groups present, org) for the preparation of a compound of the formula I in which one ofthe radicals R₁ and R₂ is thiocarbamoyl and the other substituents areas defined above for compounds of the formula I, reacting a compound ofthe formula I in which one of the radicals R₁ and R₂ is aminocarbonyland the other substituents are as defined above for compounds of theformula I, free functional groups present in the radical R if necessarybeing protected by easily removable protective groups, with Lawesson'sreagent, and then removing protective groups present, or h) for thepreparation of a compound of the formula I in which one of the radicalsR₁ and R₂ is R₁₃-thiazol-2-yl in which R₁₃ in each case is unsubstitutedor substituted lower alkyl or phenyl and the other substituents are asdefined above for compounds of the formula I, reacting a compound of theformula I in which one of the radicals R₁ and R₂ is thiocarbamoyl andthe other substituents are as defined above for compounds of the formulaI, free functional groups present in the radical R if necessary beingprotected by easily removable protective groups, with a compound of theformula IX

 in which X is a leaving group and R₁₃ in each case is unsubstituted orsubstituted lower alkyl or phenyl, free functional groups present in theradical R₁₃ if necessary being protected by easily removable protectivegroups, and then removing protective groups present, or i) for thepreparation of a compound of the formula I in which one of the radicalsR₁ and R₂ is tetrazol-5-yl and the other substituents are as definedabove for compounds of the formula I, reacting a compound of the formulaI in which one of the radicals R₁ and R₂ is cyano and other substituentsare as defined above for compounds of the formula I, free functionalgroups present in the radical R if necessary being protected by easilyremovable protective groups, with a suitable alkali metal azide, andthen removing protective groups present, or j) for the preparation of acompound of the formula I in which one of the radicals R₁ and R₂ is2-lower alkyltetrazol-5-yl and the other substituents are as definedabove for compounds of the formula I, reacting a compound of the formulaI in which one of the radicals R₁ and R₂ is tetrazol-5-yl and the othersubstituents are as defined above for compounds of the formula I, freefunctional groups present in the radical R if necessary being protectedby easily removable protective groups, with the appropriate lower alkyliodide, and then removing protective groups present, or k) for thepreparation of a compound of the formula I in which one of the radicalsR₁ and R₂ is a radical of the formula II

 in which at least one radical R₄ is lower alkylsulfonylamino,benzenesulfonylamino or toluenesulfonylamino, and the other substituentsand symbols are as defined above for compounds of the formula I,reacting a compound of the formula I in which one of the radicals R₁ andR₂ is a radical of the formula II in which at least one radical R₄ isamino and the other substituents and symbols are as defined above forcompounds of the formula I, free functional groups present in theradical R and, if present, the other radicals R₄ if necessary beingprotected by easily removable protective groups, with a compound of theformula X R₁₄—SO₂—X  (X)  in which X is chlorine or bromine and R₁₄ islower alkyl, phenyl or 4-methylphenyl, and then removing protectivegroups present, or l) for the preparation of a compound of the formula Iin which one of the radicals R₁ and R₂ is a radical of the formula II

 in which at least one radical R₄ is a radical of the formula—N═C(R₅)—R₆ in which R₅ is hydrogen and R₆ is as defined above forcompounds of the formula I and the other substituents and symbols are asdefined above for compounds of the formula I, reacting a compound of theformula I in which one of the radicals R₁ and R₂ is a radical of theformula II in which at least one radical R₄ is amino and othersubstituents and symbols are as defined above for compounds of theformula I, free functional groups present in the radical R and, ifpresent, the other radicals R₄ if necessary being protected by easilyremovable protective groups, with an acetal of the formula XI

 in which R₁₅ and R₁₆ are each individually lower alkyl or together arepentane-1,5-diyl, 3-N-lower alkyl-3-azapentane-1,5-diyl or3-oxapentane-1,5-diyl, and each R₁₇ is lower alkyl, and then removingprotective groups present, or m) for the preparation of a compound ofthe formula I in which one of the radicals R₁ and R₂ is a radical of theformula II

 in which at least one radical R₄ is N³-lower alkylureido orN³-phenylureido and the other substituents and symbols are as definedabove for compounds of the formula I, reacting a compound of the formulaI in which one of the radicals R₁ and R₂ is a radical of the formula IIin which at least one radical R₄ is amino and the other substituents andsymbols are as defined above for compounds of the formula I, freefunctional groups present in the radical R and, if present, the otherradicals R₄ if necessary being protected by easily removable protectivegroups, with an isocyanate of the formula XII R₁₈—N═C═O  (XII)  in whichR₁₈ is lower alkyl or phenyl, and then removing protective groupspresent, or n) for the preparation of a compound of the formula I inwhich one of the radicals R₁ and R₂ is a radical of the formula II

 in which at least one radical R₄ is N³-lower alkylthioureido orN³-phenylthioureido and the other substituents and symbols are asdefined above for compounds of the formula I, reacting a compound of theformula I in which one of the radicals R₁ and R₂ is a radical of theformula II in which at least one radical R₄ is amino and the othersubstituents and symbols are as defined above for compounds of theformula I, free functional groups present in the radical R and, ifpresent, the other radicals R₄ if necessary being protected by easilyremovable protective groups, with an isothiocyanate of the formula XIIIR₁₈—N═C═S  (XIII)  in which R₁₈ is lower alkyl or phenyl, and thenremoving protective groups present, or o) for the preparation of acompound of the formula I in which one of the radicals R₁ and R₂ is aradical of the formula II

 in which at least one radical R₄ is lower alkoxycarbonylamino orbenzyloxycarbonylamino and the other substituents and symbols are asdefined above for compounds of the formula I, reacting a compound of theformula I in which one of the radicals R₁ and R₂ is a radical of theformula II in which at least one radical R₄ is amino and the othersubstituents and symbols are as defined above for compounds of theformula I, free functional groups present in the radical R and, ifpresent, the other radicals R₄ if necessary being protected by easilyremovable protective groups, with a chloroformic acid ester of theformula XIV Cl—C(═O)—OR₂₀  (XIV)  in which R₂₀ is lower alkyl or benzyl,and then removing protective groups present, and after carrying out oneof the process variants a) to o), if necessary for the preparation of asalt, converting a free compound of the formula I obtained into a saltor, if necessary for the preparation of a free compound, converting asalt of a compound of the formula I obtained into the free compound. 6.A pharmaceutical composition comprising a pharmaceutically acceptablecarrier or diluent and a therapeutically effective amount of a compoundof formula I according to claim 1, or a pharmaceutically acceptable saltthereof.
 7. A method of treating tumors which are responsive to aninhibition of the tyrosine kinase activity of the receptor for EGFcomprising administering to a warm-blooded animal in need of suchtreatment a therapeutically effective amount of a compound of formula Iaccording to claim 1, or a pharmaceutically acceptable salt thereof. 8.A method of claim 7 wherein the warm-blooded animal is a human.